Exam 1 lecture 5 Flashcards
Name clinically important aminoglycosides
Tobramycin
Plazomicin
Amikacin
Gentamycin
Neomycin
Streptomycin
What do aminoglycosides have in common
Aminoglycosides are antibiotics that have core structures that are usually linked to one or more aminoglycoside rings. The core structures are streptidine and 2 deoxystreptamine
MOA of aminoglycosides
Aminoglycosides have a multifaceted MOA
1)They inhibit protein biosynthesis by binding to the 30S ribosomal subunit. They bind to the 16S rRNA forming the A site. This interferes with formation of the initiation complex, blocks further translation and elicits premature termination.
2) It also causes impairement of the proof reading function of the ribosome and formation of nonsense proteins resulting from selection of the wrong amino acids during translation. The nonsense proteins impair bacterial cell wall function.
The damaged membranes have altered permeability characteristics and actually allow transport of large amounts of aminoglycoside and protein synthesis ceases altogether.
Ultimately. the aminoglycoside leads to leakage of ions and disruption of the cytoplasmic membrane, resulting in death
How does the aminoglycoside affect the 30S ribosomal subunit
Causes a frameshift mutation. Instead of a codon CCG, a codon CGU is read, which carries a different amino acidm resulting in an altered protein formation
How do aminoglycosides enter the outer membrane of bacteria?
It involves the displacement of Mg and Ca ions that form salt bridges with phosphates of the phospholipids in the membrane. This makes the membrane more permeable to aminoglycosides (this is an active transport process)
What are the three bacterial reststance mechanisms that evolved in aminoglycoside
1) Metabolism: Bacteria inactivate aminoglycosides by acetylation, adenylation and phosphorylation. Genes responsible for metabolism can be transferred to other bacteria.
2) altered ribosomes: The 16S rRNA binding site can be altered through point mutations. This has been observed by mycobacterium tuberculosis
3) Altered aminoglycoside uptake: The rate of emergence is far less than resistance due to metabolism, and the phenotype reverts after the drug is removed
Toxicity of aminglycoside
all aminoglycosides are ototoxic (irreversible)and nephrotoxic (reversible)
Serial audiograms can be obtained for high risk patients.
Ototoxicity may lead to tinitis, high frequency hearing loss or loss of balance/ataxia
risk factors for aminoglycoside toxicities? When to discontinue the aminoglycoside?
COncurrent use of other nephrotoxic agenta like loop diyretics (ethacrynic acid and furosemide) or other neohrotoxic antimicrobial drugs (vancomycin or amphotericin)
Evidence of ototoxicity requires dx or dose adjustment
less common but serious effect of aminoglycoside?
Curare like effects like respiratory paralysis
How to reverse repiratory paralysis resulting from aminoglycosides?
Neostigimine or calcium gluconate, but mechanical respirator may be necessary
the likelihood of aminoglycoside toxicity increase with
Extended treatment period
Elderly
Renal function impairement
Higher doses
What is the therapeutic use of aminoglycosides? How are they used
They are broad spectrum against both gram + and gram -, but they are used exclusively for treatment of gram - bacteria.
They are usually given in combination with penicillins to take advantage of the synergism between these two classes. They are usually given in different arms to avoid interaction (never mix penicillin and aminoglycoside)
Why never to mic penicillin and aminoglycoside
They interact to inactivate each other
What are aminoglycosides + Penicillin used in
Bacterial endocarditis
What is streptomycin used to treat
Tuberculosis
What is the most important aminoglycoside? WHta does it treat?
Gentamycin
Used for urinary tract infections, burns and pneumonias and joint and bone infection caused by susceptible gram - infections
What to use when we encounter aminoglycoside resistant strains in hospitals
Amikacin
It has retained antibacterial activity against these resistant strains
What is amikacin synthesized from? WHat does it treat?
Amikacin is synthesized from kanamycin.
It is used competitively with gentamycin for tx of mycobacterium tuberculosis, francisella tularensis and severe pseudomonas aeruginosa infections.
It is also used to treat aminoglycoside resistant nosocomial infections in hospitals
How is tobramycin produced? What is its use?
Tobramycin is produced by fermentation of streptomyces tenebrarius.
Used parenterally to treat gentamycin resistant pseudomonas aeruginosa infections.
COmpare antimicrobial activity, PK, indication, toxicity of tobramycin and gentamycin
All similar
What are orally used aminoglycosides
Neomycin
Paromycin
How do neomycin and paromomycin work? What are they used for?
Although they are not absorbed from the GI tract, neomycin and paromomycin are used clinically to suppress gut flora in travelers darrhea and prophylactically prior to GI surgery to decrease incidence of peritonitis.
Neomycin is used as a topical ointment and paromomycin is used to treat amoebic dysentery and beef tapeworm
What is the first antibiotic to be used to cure tuberculosis
Streptomycin
How is streptomycin administered? WHat can it be used for?
Deep IM injections that are painful. Also used for bubonic plague, TB and tularemia
indication, toxicity and administration of plazomicin
Indication: Tx of complicated UTI, pyelonephritis caused by Ecoli, klebsiella pneumoniae, proteus mirabillis and enterobacter cloacae
Toxicity: Nephrotoxicitty, ototoxicity, neuromuscular blockade, teratogenicity
Administration: Administered every 24 hrs by IV for pts over 18
What are the two important parts of macrolide antibiotic? Name a macrolide antibiotic
Desosamine sugar and cladinose are two important parts. Desosamine is important for activity and has the site of protonation whereas the cladinose is less important
Erythromycin A is a macrolide antibiotic
Why are macrolide antibiotics polyketides?
They are produced by sequential addition of propionate groups to a growing chain
describe polyketide biosynthesis
Propionyl ACP and methylmalonyl ACP will react with each other, and form a product. Another methylmalonyl comes and reacts with it, forming a longer chain resulting in methyl groups on alternate carbon atoms
How is erythromycin synthesized
Propionyl-CoA reacts with saccharopolyspora erythrea to form erythronolide.
Erythronolide converges wuth deoxyhexose biosynthesis to form erythromycin
What is the pKa of the amine in erythromicin
8.8
The amine can form salts that are more solube
during peptide bond formation, describe what happens to the polypeptide attached to trna, the p site, the A site and the aminoacyl-tRNA
In peptide formation, the polypeptide attached to the tRNA in the p site of the ribosome is transferred to the aminogroup of the aminoacyl-tRNA in the A site. The ribosome then moves to the next codon, the empty tRNA is ejected and the peptidyl -tRNA is shifted from the A site to the P site (translocation) The new aminoacyl t RNA then binds the A site
How do macrolides inhibit bacteria protein synthesis
By binding reversibly to the P site of the bacterial ribosome. Thereby inhibiting translocation of peptidyl tRNA from the A site to the P site. Some macrolides also bind between the P and A sites and obstruct peptide bond formation.
are macrolide actions main;y bacteriostatic or bacteriocidal
macrolide antibiotics are mainly bacteriostatic, but can also be bactericidal in high concentrations.
What is special about how macrolides act
They tend to accumulate within leukocytes and are transported into site of infection
Describe the peptide bond formation mechanism
The amine group in the A site carries out nucleophilic attack on esther on P site.
Name the 4 resistance mechanisms against macrolides
1) lactone ester hydrolase induced to degrade the macrolides by hydrolysis of the macrocycle
2) Drug induced production of an RNA methylase. A specific adenine base (A2058) in the 23S RNA molecule of the 50 ribosomal subunit is methylated. This inhibits binding of macrolides to the 50S subunit.
Note: The erythromycin producing organism uses the same ribosomal methylation technique to protect itself from the effects of own toxic metabolites.
3) Mutation of adenine to guanine at specific site A2058. This resuts in a 10,000 fold reduction in binding of erythromycin and clarithromycin to the 23S ribosomal RNA.
4) An efflux pump ejects drugs from the cell by an active transport process
In the US, what percent if strains were resistant to macrolide antibitoics
30%
What are organisms that exhibit intrinsic resistance to macrolides, regardless of antibiotic stewardship
Pseudomonas spp
Enterobacter spp
Why is erythromycin administered as enteric coated tablets
Because the parent molecule can be inactivated under acidic conditions by 6-OH and 12-OH groups
How can we achieve acid stability for macrolides like erythromycin (dont say enteric coating)
Acid stability can be acheived with the 6-OCH derivtive which enhances oral absorption, and blocks ketal formation at low PH. The resulting antibiotic is clarithromycin
Why is azithromycin also not degraded in acidic conditions
N methylated moiety repplaces C-9 ketone so ketal formation is no longer possible and will be stable in acidic cpnditions
What is the main route of erythromycin metabolism? elimination? half life?
demethylation in liver\ is main route of metabolism
Elimination route is bile
Half life is 1.5 hrs
drug interactions of macrolides
Erthromycin and clarithromycin bind and inhibit CYP3A and related isoenzymes
macrolides have drug i/a with the following (except azithromycin)- carbamezapine, cyclosporin, disopyramide, midazolam, quinidine, rifampicin, rifabutin, theophyline, triazolam, zidovudine. The activities of these drugs are increased except rifampicin and rifabutin where acitvity of erythromycin is reduced
Ergotamine, digoxin and methylprednisolone can also have severe consequences if interacted
clinical use of erythromycin
Mycoplasma pneumoniae infetions
Legionella infection
Bordetella pertussis
campylobacter jejuni
Corynebacterium
When is erythromycin an alternative agent
Group A strep infection
Borrelia burgdorferi
Chlamydia infection and other STD
When do we use erythromycin for prophylaxis
Endocarditis
Large bowel surgery
Oral surgery
When do we use erythromycin for treatment of syndromes
Bacterial bronchitis
otitis media
Acne
Sinusitis
Pelvic inflammatory disease cased by chlamydia
side effets of macrolides
macrolides are relatively safe
1)14 memberd macrolides strongly stimulate GI motor activity and cause vomiting, cramps and abdominal pain
2) bpth minor and severe allergic skin rxn (urticaria or SJS)
3) long term use (10-20) days may cause reversible cholestatic hepatitis which manifests as jaundice with cramping, nausea and fever. condition leaves upon stopping therapy
5) Erythromycin has been shown to increase probability of pyloric stenosis in children whose mothers took the drug during late stages of pregnancy or while nursing
How are all orally administered erythromycin formulations given
Either as enteric coated capsules or tablets or as more stable salts or esters such as erythromycin ethy succinate.
