Cushman 5 Flashcards
Aminoglycoside Antibiotics
The aminoglycoside antibiotics have 1,3- ___ “core structures” that are usually linked to one or more aminoglycoside rings. The core ___ are streptidine and 2- deoxystreptamine
- diaminocyclitol
- structures
The clinically important aminoglycosides are
Tobramycin
The clinically important aminoglycosides are
Plazomicin
The clinically important aminoglycosides are
Amikacin A
The clinically important aminoglycosides are
Gentamicin C2
The clinically important aminoglycosides are
Neomycin B
The clinically important aminoglycosides are
Streptomycin
aminoglycosides: MOA
multifaceted MOA
- inhibit protein biosynthesis by binding to the ___ ribosomal subunit
- bind to the ___ rRNA forming the __ site.
- interferes with formation of the ___ complex, blocks further ___ , and elicits premature ___
- impairs ___ function of the ribosome. The formation of ___ proteins impairs bacterial cell ___ function
- The damaged membranes have altered permeability characteristics and ___ transport of aminoglycoside into the cell. Then protein synthesis ___ altogether
- Ultimately the aminoglycosides lead to ___ of ions and disruption of the cytoplasmic ___ , resulting in cell death
- can also mess with 30S to cause a ___ ___ . Results in the formation of altered ___
- 30S
- 16S, A
- initiation, translation, termination
- proofreading, nonsense, wall
- increase, stop
- leakage, membrane
- frame shift, proteins
Bacterial Aminoglycoside Uptake
1) The initial entry of the ___ charged aminoglycosides through the outer membrane involves the displacement of ___ and ___ ions that form salt bridges with phosphates of the
phospholipids in the membrane. This makes the membrane more ___ to the
aminoglycosides.
2) Passage through the cytoplasmic membrane is an ___ transport process
1) positively, Mg2+, Ca2+, permeable
2) active
Aminoglycoside Resistance
3 resistance mechanisms involved
1) ___ : Bacteria inactivate aminoglycosides by ___ , ___ , and ___ . The genes responsible for metabolism can be transferred to other bacteria. Many of the metabolizing enzymes have ___ specificity, so resistance can emerge to aminoglycosides in general
2) altered ___ : the ___ rRNA binding site can be altered through point mutations. This has been observed clinically with Mycobacterium ___
3) altered ___ : The rate of emergence is far less than resistance due to ___ , and the phenotype reverts after the drug is removed
1) metabolism, acetylation, adenylation, phosphorylation, cross-resistance
2) ribosomes, 16S
3) uptake, metabolism
T or F: human metabolize aminoglycosides
FALSE
only bacteria
Aminoglycoside Toxicity
___ (irreversible)
- Risk factors include concurrent use of other ototoxic drugs ( ___ diuretics or ___ ), compromised ___ function, or genetic vulnerability
___ (reversible)
- concurrent use with ___ diuretics or other nephrotoxic antimicrobial drugs ( ___ or ___ ) potentiate nephrotoxicity and should be avoided
Curare-like effects are less common but can result from large doses of aminoglycosides. ___ paralysis can usually be reversed by neostigmine or calcium gluconate, but mechanical assistance may be necessary. Note: calcium ___ the degree of depolarization at the neuromuscular junction caused by acetylcholine
toxicity more likely to occur if treatment is extended more than ___ days, in the elderly, if ___ function is impaired, and in higher doses.
evidence of either requires discontinuation of the drug or dosage adjustment. Use sparingly and only for specific indication
ototoxic
- loop, vancomycin, renal
nephrotoxicity
- loop, vancomycin, amphotericin
Respiratory, increases
Therapeutic Use of Aminoglycosides
Although the aminoglycosides have broad spectrum antibiotic activity against both Grams of bacteria, in practice their use is almost always reserved for treatment of Gram ____
- They are often used in combination with ___ in order to take advantage of the synergism between these two classes of antibiotics
- However, when given in combo they should be administered in ___ lines in order to avoid a chemical reaction between the two classes (results in them both being inactivated )
- negative
- PCNs
- different
Therapeutic Use of Aminoglycosides
- Penicillin/aminoglycoside combinations are used to treat bacterial ___
- ___ is most often used to treat tuberculosis.
- ___ is actually a mixture of related compounds and is the most important of the aminoglycosides. It is used for urinary tract infections, burns, some pneumonias, and joint and bone infections caused by susceptible Gram ___ infections.
- Aminoglycoside-resistant strains are common in hospitals. Fortunately, ___ has retained
antibacterial activity against these resistant strains and is therefore still useful to treat nosocomial infections
- endocarditis
- streptomycin
- gentamicin, negative
- amikacin
Aminoglycosides
Name: ___
- synthesized from ___ A. The presence of the L-hydroxyaminobuteryl amide moiety inhibits bacterial ___ by R-factors, so amikacin is more ___ than kanamycin.
- used competitively with ___ for treatment of Mycobacterium ___ , ___ tularensis, and severe ___ infections resistant to other agents.
- also used to treat aminoglycoside-resistant ___ infections in hospitals
Amikacin A
- kanamycin A, metabolism, potent
- gentamicin, TB, Francisella, P. aeruginosa
- nosocomial
Aminoglycosides
Name: ___
- produced by fermentation of ___ ___ .
- lacks a 3’- ___ group and cannot be phosphorylated at that position. However, it is ___ at C-2’ and ___ at C-3.
- Widely used parenterally to treat gentamicin-resistant ___ infections, as well as other difficult infections
- the indications, antimicrobial activity, PK properties, and a toxicity profile that are very similar to ___
Tobramycin
- Streptomyces tenebrarius
- hydroxyl, adenylated, acetylated
- P. aeruginosa
- gentamicin
Aminoglycosides
Name: ___
- mixture of several antibiotics produced by fermentation of ___ ___ and other related soil microorganisms
- It is the most important of the aminoglycoside antibiotics still in use because of its low cost and reliable activity against most resistant Gram ( ___) ____ .
- used to treat urinary tract infections, and joint and bone
infections
- ___ preparations are used to treat infections of the skin and in dressings used to treat burn patients.
- ophthalmic preparations are also used to treat eye infections
- Micromonospora purpurea
- negative, aerobes
- topical
Orally Used Aminoglycosides
Although aminoglycosides are not absorbed from the GI tract, ___ B and ___ are used clinically to suppress gut flora in ___ diarrhea and prophylactically prior to GI surgery to decrease the incidence of peritonitis.
- ___ is also used as a topical ointment
- ___ is used to treat amoebic dysentery as well as dwarf tapeworm and beef tapeworm
- Neomycin B, Paromomycin, travelers
- Neomycin B
- Paromomycin
Aminoglycosides
- produced by ___ found in soil
- It was the first antibiotic that could be used to cure ___
- administered by deep ___ injections that are often painful
- least used of the first line agents
- useful against ___ plague and tularemia
- Streptomyces griseus, TB
- IM
- bubonic
Aminoglycosides
Name: ___ (Zemdri)
- semisynthetic
- Indication: treatment of ___ urinary tract infections including ___ , caused by the following susceptible microorganisms: ___, ___ , ___ , and ___ in patients 18 years of age and older
- Toxicity: ___ , ___ , neuromuscular blockade, ___
- Administration: The recommended dosage regimen of ZEMDRI is 15 mg/kg administered every 24 hours by intravenous (IV) infusion over 30 minutes in patients 18 years of age or older
Plazomicin
- complicated, pyelonephritis
- Escherichia coli, Klebsiella pneumoniae,
Proteus mirabilis, and Enterobacter cloacae
- nephrotoxicity, ototoxicity, teratogenicity
Macrolide Antibiotics
Name: ___
1) The macrolide antibiotics are macrocyclic lactones. They are usually ___ - membered lactone
rings.
2) The ___ sugar is important for activity. The cladinose is less important.
3) Macrolide antibiotics are polyketides because they are produced by sequential addition of propionate groups to a growing ___ groups on alternate carbon atoms in the macrolide ring
4) Most are produced by ___ strains for defense. Fermentation provides a source of erythronolide that can be
used as a starting material for semisynthetic derivatives
5) The pKa of the amine in erythromycin is 8.8. The amine can form salts that are more ___
Erythromycin A
1) 14
2) desoamine
3) methyl
4) Streptomyces
5) soluble
Macrolide Antibiotics
MOA: inhibit bacterial ___ synthesis by binding ___ to the __ site of the
bacterial ribosome, thereby inhibiting ___ of peptidyl-tRNA from the A site to the P site.
- Some macrolides also appear to bind ___ the P and A sites and obstruct peptide bond formation
- Macrolide binding mainly involves the bacterial ___ RNA and not the protein
- Macrolide antibiotic action is mainly ___ , but can also be bactericidal in high concentrations
- tend to accumulate within ___ , and are therefore actually transported into the site of infection
- protein, reversible, P, translocation
- between
- bacteriostatic
- leukocytes
Macrolide Resistance
Four basic mechanisms of resistance are known:
1) ___ ___ ___ induced to degrade the macrolides by hydrolysis of the macrocycle
2) Drug-induced production of an RNA ___ - A specific adenine base (A2058) on the ___ RNA molecule of the 50S ribosomal subunit is methylated. This inhibits the binding of macrolides to the ___ subunit
3) Mutation of adenine to guanine at the specific site ___ . This results in a 10,000-fold reduction in binding of erythromycin and clarithromycin to the ___ ribosomal RNA.
4) An ___ pump ejects drugs from the cell by an active transport process.
1) Lactone ester hydrolase
2) methylase, 23S, 50S
3) A2058, 23S
4) efflux
Resistance: Macrolides
the erythromycin-producing organism uses the same ribosomal ___ technique to protect itself from the effects of its own toxic metabolite. This leads to the hypothesis that antibiotic resistance may originate in the ___ organism and then be transferred to other bacteria
- methylation
- producing
General notes on macrolide resistance:
1) Recent clinical isolates of __ ___resistant strains have been reported worldwide. In the U.S., 31% of the strains were resistant to the macrolide antibiotics in 2016.
2) Several clinical studies have correlated the ___ of use of these antibiotics with the increase of resistant ___ ___ .
3) Resistance management is especially important with regard to ___ infections
4) Certain organisms like ___ spp. and ___ spp. exhibit intrinsic resistance
by not allowing entry of these drugs.
1) Streptococcus pneumoniae
2) frequency, Streptococcus pneumonia
3) respiratory
4) Pseudomonas, Enterobacter
Macrolide: Chemical Reactivity
The parent molecule can be inactivated under ___ conditions by a process involving the 6- ___ and 12- ___ groups. The reaction is an intramolecular acid-catalyzed ketal formation. The ketal reaction product is ___ .
- Oral erythromycin is therefore administered as ___ coated tablets or as more stable salts or esters
- acidic, OH, OH, inactive
- enteric
Macrolide: Chemical Reactivity
1) Acid stability can be achieved with the 6-OCH3 derivative, which enhances ___ absorption. This ___ derivative blocks ketal formation at low pH. The resulting antibiotic is ___
2) An amine analog ( ___ ) is acid stable and has reliable absorption. In this analog an N-methylated ___ moiety replaces the C-9 ketone, so ketal formation is no longer possible
1) oral, ether, Clarithromycin
2) Azithromycin, methyleneamino
Macrolide Metabolism
The main route of erythromycin metabolism is demethylation in the ___ . Its main elimination route is in the ___ , and a small portion in the urine.
- Erythromycin’s half-life is 1.5 hours.
- liver
- bile
Macrolide Drug Interactions
Erythromycin and ___ bind and inhibit ___ and related P450 isozymes.
- Potential drug interactions can be expected with macrolides (other than ___ ) and the following drugs that are also metabolized by P450 enzymes:
- carbamazepine, cyclosporin, disopyramide, midazolam, quinidine, rifampicin, rifabutin, theophylline, triazolam, zidovudine.
The activities of these drugs are ___ due to inhibition of their metabolism except in the case of rifampicin and rifabutin, where the activity of erythromycin is reduced.
Others drugs
- ergotamine, digoxin, and methylprednisolone
- clarithromycin, CYP3A
- azithromycin
- increased
Clinical Use of Erythromycins
Erythromycins are primarily used for infections of ___ and ___ tissues primarily caused by Gram ( ___ ) bacteria
Drug of Choice:
- Mycoplasma pneumoniae infections
- Group A streptococcal upper respiratory tract infection (penicillin-allergic patient)
- Legionella infection
- Bordetella pertussis
- Campylobacter jejuni
- skin, soft +
Macrolide SE
1) Macrolides are relatively ___
2) The ___ -membered macrolides strongly ___ gastrointestinal motor activity and can cause vomiting, gastric cramps and abdominal pain.
3) Both minor and severe allergic skin reactions (rashes) are known. Allergic reactions may range from urticaria (hives) to anaphylaxis. ___ syndrome and toxic epidermal necrolysis are serious side effects that are rare but may occur.
4) Long term use (10-20 days) can induce a ___ cholestatic ___ which will manifest as a ___ with cramping/nausea/fever
5) Erythromycin has been shown to increase the probability of pyloric ___ in children whose mothers took the drug during the late stages of pregnancy or while nursing
1) safe
2) 14
3) stimulate
4) reversible, hepatitis, jaundice
5) stenosis
Pharmacokinetics
- Since erythromycin is inactivated by ___ acids, all orally administered formulations are given as either ___ coated capsules or tablets, or as more stable salts or esters such as erythromycin ethyl succinate.
- Erythromycin is very rapidly absorbed and diffuses into most tissues and ___ . Due to the high concentration in phagocytes, erythromycin is actively
transported to the site of infection - The phagocytes therefore provide a very efficient drug delivery
mechanism!
- gastric, enteric
- ## phagocytes
