Exam 1 lecture 5

Question 1

Name clinically important aminoglycosides

Answer 1

Tobramycin
Plazomicin
Amikacin
Gentamycin
Neomycin
Streptomycin

Question 2

What do aminoglycosides have in common

Answer 2

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

Question 3

MOA of aminoglycosides

Answer 3

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

Question 4

How does the aminoglycoside affect the 30S ribosomal subunit

Answer 4

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

Question 5

How do aminoglycosides enter the outer membrane of bacteria?

Answer 5

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)

Question 6

What are the three bacterial reststance mechanisms that evolved in aminoglycoside

Answer 6

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

Question 7

Toxicity of aminglycoside

Answer 7

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

Question 8

risk factors for aminoglycoside toxicities? When to discontinue the aminoglycoside?

Answer 8

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

Question 9

less common but serious effect of aminoglycoside?

Answer 9

Curare like effects like respiratory paralysis

Question 10

How to reverse repiratory paralysis resulting from aminoglycosides?

Answer 10

Neostigimine or calcium gluconate, but mechanical respirator may be necessary

Question 11

the likelihood of aminoglycoside toxicity increase with

Answer 11

Extended treatment period
Elderly
Renal function impairement
Higher doses

Question 12

What is the therapeutic use of aminoglycosides? How are they used

Answer 12

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)

Question 13

Why never to mic penicillin and aminoglycoside

Answer 13

They interact to inactivate each other

Question 14

What are aminoglycosides + Penicillin used in

Answer 14

Bacterial endocarditis

Question 15

What is streptomycin used to treat

Answer 15

Tuberculosis

Question 16

What is the most important aminoglycoside? WHta does it treat?

Answer 16

Gentamycin

Used for urinary tract infections, burns and pneumonias and joint and bone infection caused by susceptible gram - infections

Question 17

What to use when we encounter aminoglycoside resistant strains in hospitals

Answer 17

Amikacin

It has retained antibacterial activity against these resistant strains

Question 18

What is amikacin synthesized from? WHat does it treat?

Answer 18

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

Question 19

How is tobramycin produced? What is its use?

Answer 19

Tobramycin is produced by fermentation of streptomyces tenebrarius.

Used parenterally to treat gentamycin resistant pseudomonas aeruginosa infections.

Question 20

COmpare antimicrobial activity, PK, indication, toxicity of tobramycin and gentamycin

Answer 20

All similar

Question 21

What are orally used aminoglycosides

Answer 21

Neomycin
Paromycin

Question 22

How do neomycin and paromomycin work? What are they used for?

Answer 22

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

Question 23

What is the first antibiotic to be used to cure tuberculosis

Answer 23

Streptomycin

Question 24

How is streptomycin administered? WHat can it be used for?

Answer 24

Deep IM injections that are painful. Also used for bubonic plague, TB and tularemia

Question 25

indication, toxicity and administration of plazomicin

Answer 25

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

Question 26

What are the two important parts of macrolide antibiotic? Name a macrolide antibiotic

Answer 26

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

Question 27

Why are macrolide antibiotics polyketides?

Answer 27

They are produced by sequential addition of propionate groups to a growing chain

Question 28

describe polyketide biosynthesis

Answer 28

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

Question 29

How is erythromycin synthesized

Answer 29

Propionyl-CoA reacts with saccharopolyspora erythrea to form erythronolide. Erythronolide converges wuth deoxyhexose biosynthesis to form erythromycin

Question 30

What is the pKa of the amine in erythromicin

Answer 30

8.8 The amine can form salts that are more solube

Question 31

during peptide bond formation, describe what happens to the polypeptide attached to trna, the p site, the A site and the aminoacyl-tRNA

Answer 31

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

Question 32

How do macrolides inhibit bacteria protein synthesis

Answer 32

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.

Question 33

are macrolide actions main;y bacteriostatic or bacteriocidal

Answer 33

macrolide antibiotics are mainly bacteriostatic, but can also be bactericidal in high concentrations.

Question 34

What is special about how macrolides act

Answer 34

They tend to accumulate within leukocytes and are transported into site of infection

Question 35

Describe the peptide bond formation mechanism

Answer 35

The amine group in the A site carries out nucleophilic attack on esther on P site.

Question 36

Name the 4 resistance mechanisms against macrolides

Answer 36

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

Question 37

In the US, what percent if strains were resistant to macrolide antibitoics

Answer 37

30%

Question 38

What are organisms that exhibit intrinsic resistance to macrolides, regardless of antibiotic stewardship

Answer 38

Pseudomonas spp Enterobacter spp

Question 39

Why is erythromycin administered as enteric coated tablets

Answer 39

Because the parent molecule can be inactivated under acidic conditions by 6-OH and 12-OH groups

Question 40

How can we achieve acid stability for macrolides like erythromycin (dont say enteric coating)

Answer 40

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

Question 41

Why is azithromycin also not degraded in acidic conditions

Answer 41

N methylated moiety repplaces C-9 ketone so ketal formation is no longer possible and will be stable in acidic cpnditions

Question 42

What is the main route of erythromycin metabolism? elimination? half life?

Answer 42

demethylation in liver\ is main route of metabolism Elimination route is bile Half life is 1.5 hrs

Question 43

drug interactions of macrolides

Answer 43

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

Question 44

clinical use of erythromycin

Answer 44

Mycoplasma pneumoniae infetions Legionella infection Bordetella pertussis campylobacter jejuni Corynebacterium

Question 45

When is erythromycin an alternative agent

Answer 45

Group A strep infection Borrelia burgdorferi Chlamydia infection and other STD

Question 46

When do we use erythromycin for prophylaxis

Answer 46

Endocarditis Large bowel surgery Oral surgery

Question 47

When do we use erythromycin for treatment of syndromes

Answer 47

Bacterial bronchitis otitis media Acne Sinusitis Pelvic inflammatory disease cased by chlamydia

Question 48

side effets of macrolides

Answer 48

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

Question 49

How are all orally administered erythromycin formulations given

Answer 49

Either as enteric coated capsules or tablets or as more stable salts or esters such as erythromycin ethy succinate.