Week 4 - Antibiotics: Inhibitors of Protein Synthesis Flashcards
Protein synthesis inhibitors.. Selective toxicity
Bind and inhibit prokaryotic ribosome without blocking eukaryotic ribosome
What are the 30S inhibitors of protein synthesis?
30S inhibitors include aminoglycosides and tetracycline
What are the 50S inhibitors of protein synthesis?
50S inhibitors include linezolid, macrolides, chloramphenicol, clindamycin, quinupristin/dalfopristin
What are the different steps that the antibiotics inhibit during translation of mRNA to protein?
Initiation- linezolid, aminoglycosides Elongation- aminoglycoside, tetracycline, macrolide,chloramphenicol, clindamycin, quinupristin/dalfoprisitin Termination- aminoglycoside
Most ribosome inhibitors are ____________?
Note: Most ribosome inhibitors are bacteriostatic Linezolid, tetracycline and chloramphenicol interfere with mitochondrial ribosomes (bone marrow suppression)
What are the initiation steps of translation in prokaryotes?
Initiation in Prokaryotes
- Initiation factors associate with the 30S ribosomal subunit.
- Formylmethionine initiator tRNA and mRNA bind to 30S subunit.
- 50S ribosome then binds and you have the complete initiation complex.
Where does Linezolid bind to do inhibit translation?
The P-site on the 50S
Where do aminoglycosides bind to in order to inhibit translation?
The 30S ribosome and freezes the initiation complex
Oxazolidinones
Mechanism
Spectrum
Resistance
Adverse Effects
Important fact
Linezolid Mechanism: Bacteriostatic- Inhibits protein synthesis by binding to the 23S ribosomal RNA on the 50S subunit and preventing formation of the initiation complex.
Spectrum: Reserved for treatment of drug resistant Gram+ including MRSA, Vancomycin Resistant Enterococci
Resistance: alterations or modifications in 23S ribosomal RNA It has a unique binding site on the 50S ribosome, resulting in no cross-resistance with other drug classes. (alteration of drug target on ribosome)
Adverse Effects: Bone marrow suppression, inhibits monoamine oxidase which can lead to serotonin syndrome
Important Facts: Excellent bioavailability
What is the spectrum of oxazolidinones (Linezolid)?
Spectrum: Reserved for treatment of drug resistant Gram+ including MRSA, Vancomycin Resistant Enterococci
What are the aminoglycosides?
gentamicin, neomycin, amikacin, tobramycin, streptomycin
Aminogoycosides Mechanism Spectrum Resistance
Mechanism: Bactericidal- Prevents formation of initiation complex, causes misreading of mRNA, and induces early termination.
Spectrum: Gram- aerobic
Resistance:
Intrinsic resistance- failure of antibiotic to enter bacterial cell
Acquired resistance- Mutations on 30S ribosome or expression of ribosomal methyltransferases Acquisition of enzymes which inactivate the drug through acetylation, phosphorylation, or adenylation
Amikacin- less susceptible to enzyme inactivation and broader spectrum including Pseudomonas
What is unique about the aminoglycoside Amikacin?
Amikacin- less susceptible to enzyme inactivation and broader spectrum including Pseudomonas
What is the mechanism of action for aminoglycosides?
Binds to 30S ribosome
Explain the dosing of aminoglycosides
Add Pic administered as single large dose:
Concentration-dependent killing and post antibiotic effects
Concentration-dependent: Concentrations are > 10 times above the MIC most effective at killing the organism (aminoglycosides are concentration dependent*)
Time-dependent: effect depends on time above the MIC (beta-lactams need to have multiple doses, they are time dependent*)
MIC - minimun inhibitory complex
What are the adverse effects and important facts of aminoglycosides?
Adverse Effects:
Tubular necrosis:
nephrotoxicity- drug retained in renal cortex
ototoxicity- vestibular and auditory dysfunction teratogen- hearing loss in fetus so don’t use during pregnancy*
Facts: Drugs are small and polar excluded from CSF Uptake of Aminoglycosides is blocked by anaerobic conditions so strict anaerobes and facultative bacteria in anaerobic conditions are intrinsically resistant.
Can be synergetic with Penicillin
Poor gut absorption usually administered by IV
Gentamicin is synergentic with penicilian*
Which of the following aminoglycoside is most effective against Serratia?
Kanamycin
Gentamicin
Netilmicin
Tobramycin
Amikacin
Gentamicin - has the lowest MIC from the table.
When would want to use amikacin instead of gentamicin? for Pseudomonas. Or if worried about bacteria expressing the enzymes that … the aminoglycosides..
Aminoglycoside antibiotics are:
Bactericidal for Gram-positive bacteria
Modified by methyltransferases
Bind to the 50S ribosomal subunit
Time-dependent inhibitors Require bacterial growth to be effective
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What are the steps in chain elongation of proteins?
- Aminoacyl tRNA is inserted in the acceptor site. Tetracyclines interfere here and prevent aminoacyl tRNA attachment to the acceptor site.
- The peptide bond is formed. Chloramphenicol inhibits peptide bond formation.
- fmet tRNA is released from the P site. In prokaryotes, an exit site called the E site binds tRNA after it’s displaced from the P site
- Translocation. A dipeptide tRNA moves from the A to the P site and the ribosome moves one codon along the mRNA. Macrolides, Streptotagmins, Clindamycin inhibit translocation.
- Another amino acyl tRNA is put in the A site and elongation continues.
What do tetracyclines interfere with during chain elongation?
Tetracyclines interfere here and prevent aminoacyl tRNA attachment to the acceptor site.
What does chloramphenicol inhibit during chain elongation?
Chloramphenicol inhibits peptide bond formation.
What do macrolides, streptotagmins, and clindamycin inhibit during chain elongation of proteins?
Macrolides, Streptotagmins, Clindamycin inhibit translocation
Tetracyclines- tetracycline, doxycycline, minocycline
Mechanism
Spectrum
Resistance
Mechanism: Bacteriostatic-bind 30S preventing attachment of aminoacyl-tRNA
Spectrum: Broad initially but due to resistance only a few: B. burgdorferi, H. pylori (alsers), Mycoplasma pneumoniae.
Resistance: Intrinsic: decreased uptake
Acquired: Increased efflux* Alteration of ribosomal target Rarely enzymatic inactivation of drug (acetyl)
What are adverse effects of tetracyclines?
Adverse effects: form stable chelates with a number of metal ions such as calcium, magnesium, iron and aluminum decreasing gut absorption of the drug.
Gastrointestinal irritation and photosensitivity (abnormal sunburn reaction)
Discoloration of teeth and inhibits bone growth in children.
Pregnancy class D (should not be used)*
Which of the following antibacterial drugs, that we discussed previously, should not be consumed with milk or antacids due to the formation of an insoluble complex between the drug and cations
A. Nitrofurantoin
B. Ciprofloxacin
C. Metronidazole
D. Penicillin G
E. Rifampin
B. Ciprofloaxacin - fluoroquinolones class
What is mycoplasma pneumonia?
atypical pneumonia
Use: Doxycycline, Azithromycin, Levofloxacin
Beta-lactams are not effective* (no cell wall)
A 32-year-old woman has a 6 day history of fever and fatigue. She recently noticed an unusual rash on her leg that has spread rapidly prompting her to see her physician. She lives in a wooded area outside of Moose Lake. What’s your diagnosis and the causative agent?
Use the John Hopkin’s guide to find the recommended antibiotics for early treatment of the
disease
Lymes Disease
Tic is injecting the bacteria Borrelia burgdorferi into the human
Johs hopkins guide: Amoxicillian or Doxycyclines
Chloramphenicol
Mechanism
Spectrum
Resistance
Mechanism: Bacteriostatic- binds 50S preventing peptide bond formation- peptidyltransferase can’t associate with amino acid substrate
Spectrum: Extended but use is limited due to severe side effects Resistance: acetyltransferase modifies drug to prevent binding to the ribosome
Resistance: acetyltransferase modifies drug to prevent binding to the ribosome
What are the adverse effects of chlormphenicol?
Adverse effects: TOXIC Bone marrow depression and aplastic anemia
Gray baby syndrome- premature infants lack the enzyme UDP-glucuronyl transferase and have decreased renal function so high levels of the drug accumulate, which can lead to cardiovascular and respiratory collapse
What is grey baby syndrome?
Gray baby syndrome- premature infants lack the enzyme UDP-glucuronyl transferase and have decreased renal function so high levels of the drug accumulate, which can lead to cardiovascular and respiratory collapse
What are the macrolides?
Macrolides- erythromycin, azithromycin, clarithromycin
Macrolides Mechanism Spectrum
Mechanism: Bacteriostatic Inhibits translocation by binding 23S rRNA of the 50S subunit
Spectrum: Broad coverage of respiratory pathogens, Chlamydia
Macrolides Resistance Adverse effects
Resistance: methylation of 23S rRNA binding site- also associated with clindamycin and quinupristin/dalfopristin resistance increased efflux hydrolysis of the the macrolide by esterases
Adverse effects: GI discomfort, Hepatic failure, and Prolonged QT interval
Inhibitors of cytochrome P450 enzymes (check with other medications)
Clarithromycin is not safe during pregnancy*
Lincosamide
Mechanism
Spectrum
Resistance
Adverse effects
Lincosamide: Clindamycin Mechanism: Bacteriostatic- blocks translocation at 50S ribosomal subunit
Spectrum: Gram positive including anaerobic. Treat acne.
Resistance: mutation of ribosome, methylation of ribosomal RNA, Cross resistance with macrolides and streptogramins inactivation of drug by adenylation
Adverse effects: Hypersensitivity: rash and fever Diarrhea, abdominal pain, mucus and blood in stool
Superinfection with C. difficile*
What are the streptogramins?
Quinupristin/Dalfopristin
Streptogramin
Mechanism
Spectrum
Resistance
Adverse Effects
Quinupristin/Dalfopristin
Mechanism: Combined action is bactericidal for some organisms. Binds 50S to inhibit translocation.
Spectrum: Quinupristin/dalfopristin should be reserved for infections caused by multiple drug-resistant G+ bacteria*
Resistance: Ribosomal methylase prevents binding of drug to its target. Enzymes inactivate the drugs. Efflux proteins that pump them out of the cell. Cross resistance with macrolides and clindamycin.
Adverse Effects: High incidence including arthralgias and myalgias are common. Inhibits a cytochrome P450 enzyme and is likely to have significant drug interactions.
Review: Write the mechanism of action for the following inhibitors include where the drug binds and resistance
Name specific agents for Aminoglycosides, Tetracyclines, Macrolides, Streptogramins Linezolid Aminoglycosides Tetracyclines Chloramphenicol
Linezolid - Bacteriostatic. inhibits protein syntheis, binds to 50S ribosomal subunit. Resistance - alterations of UNIQUE binding site (no cross resistace)
Aminoglycosides - Bactericidal. Prefents initiation complex inducint early termination (multiple steps inhibited - thats whey bactericidal). Resistance - failur to enter cell. Mutations of 30S, bacterial enzymes,
Tetracyclines - Bacteriostatic. Bind to 30S preventing attachment of tRNA. Reistance - decreased uptake (alteration of target site). Increased efflux*
Chloramphenicol - Bacterio static - binds to 50S. prevents protein formation. Resistance - Modifies drug to prevent binding
Write the mechanism of action for the following inhibitors include where the drug binds and resistance
Name specific agents for Aminoglycosides, Tetracyclines, Macrolides,
Aminoglycosides
Tetracyclines
Mactrolides
Streptogramins
Enterococcus Resistance
A 42 year old male presents with a ruptured appendix and peritonitis resulting in severe infection with both aerobic and anaerobic Gram negative organisms. Why is monotherapy with an aminoglycoside inappropriate? What drugs are effective against anaerobic organisms?
Why is monotherapy with an aminoglycoside inappropriate?
-Because it needs energy to enter cell so it would not cover the anaerobic microbes
What drugs are effective against anaerobic organisms?
Vancomycin
Metrozonol
Which of the following contributes to gray baby syndrome when chloramphenicol is administered to neonates?
Decreased intestinal absorption
Increased glomerular filtration
Lack of CNS penetration
Alteration of gastrointestinal flora by a broad spectrum antibiotic
Low hepatic glucuronyl transferase activity
Low hepatic glucuronyl transferase activity.. babys do not have this enzyme…
Treatment of a bacterial culture with an antibacterial drug results in the cytoplasmic accumulation of monosomes (have block before 50S is added so only get one ribosome subunit on the mRNA). The antibacterial drug is most likely:
Amikacin
Azithromycin
Ciprofloxacin
Meropenem
Tetracycline
Amikacin - it blocks the formation of the inititation complex (binds to 30S subunit)
Your initial treatment with tetracycline is ineffective so you switch to erythromycin. Unfortunately, your patient still doesn’t respond to the new therapy. This is mostly likely because of resistance due to:
Enzymatic degradation of the drugs
Active efflux of the drugs from the bacteria by a transporter
Modification of the 50 S ribosomal subunit by methyltransferase preventing binding of the drugs
Acetylation of the drugs
Overproduction of the ribosomal target
Active efflux of the drugs.
It is not C because they both do not bind to 50S, one binds to 50 the other to 30
NB is a 21-year-old college football player (linebacker) who presents to the clinic with a large, red abscess on his right arm, likely due to community-acquired methicillin-resistant Staphylococcus aureus. It is lanced and drained, and antibiotic therapy is to be prescribed. Which drug would be the most appropriate choice for NB’s infection? He is to be treated as an outpatient.
A. Cephalexin
B. Ciprofloxacin
C. Erythromycin
D. Vancomycin
E. Linezolid
Linezolid - Can also be used for MRSA
Vanco is good but it is bad for oral (out pt)
Identify the drugs that are reserved for infections due to hard to treat drug resistant bacteria like MRSA and VRE (vancomycin resistant enterococcus)
5th gen cephalosporin- ceftaroline, vancomycin, TMP-SMX, daptomycin, Quinupristin-Dalfopristin, Linezolid
Your patient has a suppressed immune system which of the following antibiotics is the best choice for your patient.
A. Doxycycline
B. Gentamicin
C. Erythromycin
D. Linezolid
E. Clindamycin
B - Gentamicin
It is bacteriocidal… not bacterial static
Bacterial static drugs rely on immune system to come and take up the bacteria after their replication has been inhibited becasue they are not dead yet..
A 30 year old woman who is pregnant has a severe lung infection. She needs to be treated with an antibiotic. Assume each of the following is effective against the bacteria in question. Which would you choose?
Azithromycin
Clarithromycin
Gemifloxacin
Minocycline
Moxifloxacin
A. Azithromycin
Mox and gem are fluoroquinolones
Minocyclin is bad on teeth
Azith and clari are in same class but clarith is bad for prego.
Identify the antibiotics for the following:
Dont use with newborns
Dont use in children
Dont use during pregnancy
In the elderly, adjust for reduced renal function
Don’t use with Newborns Chloramphenicol (can’t glucuronidate) Erythromycin (pyloric stenosis)
Don’t use in children Tetracyclines, Fluoroquinolones
Don’t use during Pregnancy Tetracycline, Aminoglycosides, Clarithromycin, Fluoroquinolones, Chloramphenicol
In the elderly, adjust for reduced renal function. The half life of beta lactams, aminoglycosides and fluoroquinolones will be increased.
What are antibiotics that may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency?
Sulfonamides (Trimethoprim/Sulfamethoxazole). It will cause hemolysis..
A 23-year old female is being treated for a severe infection in the hospital. Every time she gets up and attempts to move around her room, she loses her balance. The antibiotic treatment that is most likely responsible for her symptom is:
Gemifloxacin
Linezolid
Piperacillin
Quinupristin/ dalfopristin
Tobramycin
E. Tobramycin - kidney and otto imbalances…
What antibiotics are associated with the following?
Seizures
Hepatotoxicity
Nephrotoxicity
Ototoxicity
QTc interfal prolongation
Anemia
Arthralgia
Disulfiram
Superinfection
Seizures: beta-lactams (particularly carbapenems) Hepatotoxicity: Rifampin Nephrotoxicity: Sulfonamides, Aminoglycosides, Vancomycin Ototoxicity: Aminoglycosides, Vancomycin QTc interval prolongation: macrolides, fluoroquinolones Anemia: Chloramphenicol, Trimethoprim Arthralgia: Quinupristin/dalfopristin, Fluoroquinolones Disulfiram-reaction when taken with alcohol: metronidazole,2nd gen Cephalosporin with methylthiotetrazole groups Superinfection: Clindamycin, fluoroquinolones, 3rd gen Cephalosporin, Ampicillin
Sulfonamides Patients should not be given other sulfa drugs such as diuretics Beta-lactam Skin test can be used to confirm and patient can be desensitized Clindamycin Which of the following beta-lactams is least likely to cause an allergic reaction?
A. Aztreonam
B. Penicillin
C. Cephalosporin
D. Carbapenem
Aztreonam
What antibiotics have drug-drug interactions?
Rifampin induces drug metabolizing enzymes
Clarithromycin and Erythromycin inhibit hepatic metabolism
Combination drug therapy:
- Enhancement of antibacterial activity in the treatment of specific infections (synergism) Trimethoprim – Sulfamethoxazole Inhibits multiple steps in folate synthesis Aminoglycoside + Penicillin Penicillin increases permeability of cell membranes increasing the ability of aminoglycosides to enter the cell
- Treatment of mixed bacterial infections caused by two or more microbes.
- Therapy of severe infections in which a specific etiology is unknown. Not to be used as a shortcut but used until clinical and lab data allow the selection of a specific antimicrobial
- Prevention of the emergence of resistant organisms. Treatment of Tuberculosis
- Addition of inhibitors to prevent degradation of the enzyme Ampicillin-sulbactam, Amoxicillin-clavulanate, Piperacillin-tazobactam, Ticarcillin-clavulanate Imipenem-cilastatin (blocks renal dehydropeptidase)
What are the drawbacks of using drugs in combination?
- Risk of toxicity from two agents Vancomycin or Aminoglycosides each alone have some nephrotoxicity. If given together you get marked renal impairment.
- Antagonism Pneumococcal meningitis Penicillin - 21% mortality Penicillin + Tetracycline - 79% mortality
- Selection of microorganisms resistant to antibiotics
- Superinfection
- Extra cost
What are the guidlines for effective treatment?
Avoid using antibiotics to treat colonization of contamination
Goal to use narrow-spectrum agent that is effective
Use the proper dose if exposed to low concentrations that don’t kill more likely to develop resistance
Use the shortest effective duration of therapy
Prokaryote vs Eukaryote Ribosome differences
Prokaryote: 30S and 50S start with formyl methionine - AUG Shine Delgarno sequence Eukaryotes 40S and 60S Start with methionine - AUG and 5’ cap
How do bacteria become resistant to vancomycin?
Changes the end of the aminoglycan sugar group? look this one up.
Which of the following is true regarding aminoglycosides?
Bactericidal for gram-pos
modifiec by methyltranferases
bind to 50S ribosomal subunit
Time-dependent inhibitors
require energy to be effective
Bacterialcidal with pennicilian
Enzyme inhibitors
Bind to 30S
It is a concentration depentent inhibitor (get hight does above MIC vs just being above the MIC for a long time)
Yes. E.
Steps to prescribe antibiotics…
Step 1: Identify the type of infection. Where and what organism?
Symptoms- key, subjective effects felt by patient like pain
Signs are objective evidence-rash
Time course- bacterial meningitis is acute vs.
fungal meningitis may take a few weeks.
Diagnostic tests- often incorporate properties of organisms
Epidemiology- organisms most likely to infect particular age group as well risk factors like HIV status, tick exposure
Step 2: Where and how is the person infected?
Transmission
Microbiology organism virulence factors evade host defense
Pathology damage to the host and possible sequelae associated with this organism
Step 3: How should the infection be managed?
Prevention: strategies to inhibit transmission
Mechanism & Spectrum: how do antimicrobials work and what organisms are they effective against
Pharmacology: ADME, Need a drug that can get to the microorganism
Patient factors: Pregnant, immunocompromised
Is the organism resistant against certain antibiotics?
