Antibiotics Flashcards
Protein Synthesis Inhibitors
Selective toxicity
Bind and inhibit prokaryotic ribosome without blocking eukaryotic ribosome
Linezolid, aminoglycosides, tetracycline, macrolides, chloramphenicol, clindamycin, quinupristin/dalfopristin
30S Inhibitors
30S inhibitors include aminoglycosides and tetracycline
50S
50S inhibitors include linezolid, macrolides, chloramphenicol, clindamycin,
quinupristin/dalfopristin
Initiation in Prokaryotes
Which AB’s prevent Initiation in PS?
1) Initiation factors associate with the 30S ribosomal subunit.
2) Formylmethionine initiator tRNA and mRNA bind to 30S subunit.
3) 50S ribosome then binds and you have the complete initiation complex.
* Linezolid binds to the P-site on the 50S
* Aminoglycosides bind to the 30S ribosome and freeze the initiation complex.
Which Protein Synthesis Inhibitor is bactericidal?
Aminoglycosides; they inhibit both in initiation, elongation and termination - basically everywhere in PS
Oxazolidinones- 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: Gram+ including MRSA, Vancomycin Resistant Enterococci
Resistance: 23S ribo RNA changes
UNIQUE binding site - does NOT result in cross-resistance with other drug classes.
Adverse Effects: Bone marrow suppression,
Inhibits monoamine oxidase which can lead to Serotonin Syndrome
Important Facts: Excellent bio-availability
What’s the mechanism through which Enterococci become resistant to vancomycin?
Change in binding site…
Aminoglycoside examples & mechanism & spectrum
gentamicin, amikacin, tobramycin, neomycin, streptomycin
Bactericidal- Prevents formation of initiation complex, causes misreading of mRNA, and induces early termination.
Gram-NEGATIVE only
Aminoglycoside Resistance
Which one is less susceptible?
What leads to less resistance & bactericidal activity?
Intrinsic resistance- failure of antibiotic to enter bacterial cell (anaerobic)
Acquired resistance-
Acquisition of enzymes which inactivate the drug through acetylation, phosphorylation, or adenylation
Amikacin- less susceptible to enzyme inactivation and broader spectrum
including Pseudomonas
alteration to proteins in cell membrane
Aminoglycoside Mechanism image
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Concentration-dependent:
Aminoglycosides administered as single large dose:
Concentrations are > 10 times above the MIC most effective at killing the organism
Time-dependent:
Time-dependent: effect depends on time above the MIC (BETA-LACTAMS need to have multiple doses)
Aminoglycosides: use limited due to side effects
Adverse Effects:
Tubular necrosis:
nephrotoxicity- drug retained in renal cortex (reversible)
ototoxicity- vestibular and auditory dysfunction (irreversible)
pregnancy class D- hearing loss in fetus
Important Facts:
Poor gut absorption usually administered by IV
Drugs are polar and excluded from CSF
Gentamicin is synergetic with Penicillin and used in the treatment of some Gram positive organisms - pen’s weaken cell wall –> better uptake of aminoglycocides to inhibit PS.
When would one want to use amikacin over gentimycin?
pseudamonas and when resistance exists due to enzyme inactivation
Why are aminoglycosides not as affective against anaerobes?
Requires GTP to enter cell
Elongation inhibitors
- Aminoacyl tRNA is inserted in the acceptor site. *TETRACYCLENES 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.
Tetracycline examples, mechanism and spectrum
tetracycline, doxycycline, minocycline
Mechanism: Bacteriostatic-bind 30S preventing attachment of aminoacyl-tRNA
Spectrum: Broad initially
but due to resistance
B. burgdorferi, H. pylori, Mycoplasma pneumoniae.
Due to resistance, tetracyclines have niche uses:
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Tetracylcines and resistance
Resistance: Intrinsic: decreased uptake Acquired: Increased efflux* Alteration of ribosomal target Rarely enzymatic inactivation of drug (acetyl)
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)
- 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?
Lyme’s Disease due to Borrelia burgdorferi. Erythema migrans (bulls eye rash). Tx w/ amoxicillin, doxy or cefuroxime.
Chloramphenicol Mechanism, spectrum and 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
Chlloramphenicol SERIOUS AE’s
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
Macrolides examples, mechanism and spectrum
erythromycin, azithromycin, clarithromycin
Mechanism: Bacteriostatic
Inhibits translocation by binding 23S rRNA of the 50S subunit
Spectrum: Broad coverage of respiratory pathogens, Chlamydia (single dose)
What AB’s are effective in tx atypical pneumonia?
Mycoplasma pneumonia - Doxycycline, Azithromycin, Levofloxacin
Beta-lactams are not effective
Macrolide resistance & AE’s
Use of Macrolides is limited by:
Resistance:
methylation of 23S rRNA binding site- also associated with clindamycin and quinupristin/dalfopristin resistance
increased efflux (like tetracyclines)
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) –> higher levels of other drugs (opposite of rifampin)
Clarithromycin is not safe during pregnancy
Lincosamide: Clindamycin, mechanism & spectrum
Mechanism: Bacteriostatic- blocks translocation at 50S ribosomal subunit
Spectrum: Gram positive including anaerobic. Treat acne.
Clinda Resistance & AE’s
Adverse effects:
Hypersensitivity: rash and fever (like pens & SMX)
Diarrhea, abdominal pain, mucus and blood in stool
Superinfection with C. difficile*
Resistance: mutation of ribosome, methylation of ribosomal RNA (D-test), Cross resistance with macrolides and streptogramins
inactivation of drug by adenylation
Streptogramins: Quinupristin/Dalfopristin Mech & Spectrum
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.
Streptogramins: Quinupristin/Dalfopristin
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.
Compare MOA’s & resistance mech’s of Linezolid, Aminoglycosides, Tetracyclines and Chloramphenicol
Aminos: 30S - initiation, elongation & term; upreg of eflux & target site alt
Linz: 23S of 50S - prevents form of init complex
Tet: 30S - attachment of aminoacyl-tRNA
Chlor: 50S - bond formation- peptidyltransferase
Compare MOA’s & resistance mech’s of Macrolides, Clindamycin and Streptogramins
Macs: Inhibs translocation - 23S rRNA/50S
Clinda: translocation at 50S riboso
Strepts: translocation at 50S ribosomal
Get cross-resistance by alt of target ribo site; eflux
Enterococcus resistance
great overview slide
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?
Amino’s
Which of the following contributes to gray baby syndrome when chloramphenicol is administered to neonates?
Low hepatic glucuronyl transferase activity
Treatment of a bacterial culture with an antibacterial drug results in the cytoplasmic accumulation of monosomes (single subunits on mRNA). The antibacterial drug is most likely:
Gotta be an initiation inhibitor - either aminoglycoside (like gent, tobra or amikacin) or linezolid.
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:
Binding cites are different with these two, so eflux is likely cause of cross resistance. Macs, clinda & Streptogramins: Quinupristin/Dalfopristin show cross resistance due to target site alteration in 50S translocation.
Review mechanisms of resistance: DRUG DOES NOT REACH ITS TARGET
Primarily decreased uptake
- Tetracyclines
- Sulfonamides
- Aminoglycosides
- Chloramphenicol
Increased efflux
Cephalosporins Aztreonam Tetracyclines (most impt), minocycline the exception Macrolides Quinupristin/dalfopristin Fluoroquinolones Sulfonamides
TARGET IS ALTERED
Altered Target
Beta-lactams – altered penicillin binding proteins (MRSA)
Vancomycin- altered target
Rifampin - DNA dependent RNA polymerase
Fluoroquinolones - DNA topoisomerase II or IV
Sulfonamides - Dihydropteroate synthetase
Trimethoprim - Dihydrofolate reductase
Linezolid – altered ribosome
Aminoglycosides – altered ribosome (uncommon)
Erythromycin, clindamycin, quinupristin/dalfopristin – methyltransferase modified ribosome
Tetracyclines – production of proteins that interfere with ribosomal binding
Upregulation of target or its substrate
Sulfonamides- Increased levels of para-amino benzoic acid synthesis
DRUG IS NOT ACTIVE
Penicillins beta-lactamases
Cephalosporins beta-lactamases
Aminoglycosides Amikacin most resistant, acetyl group
Chloramphenicol Acetyltransferase action
Tetracyclines minor- acetylation
Macrolides bacterial esterases
Clindamycin adenylation
quinupristin/dalfopristin
metronidazole decreased drug activation
Rarely Occurs
Bacitracin
Polymyxins
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.
Linezolid or ____ or _____. Vanc has poor bioavail = no PO version
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, daptomycin, Quinupristin-Dalfopristin, Linezolid
Your patient has a severe infection and a suppressed immune system which of the following antibiotics is the best choice for your patient.
want to use a bactericidal drug in this case. Gentamicin (an aminoglycoside) would make sense.
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?
Azythromycin. Not clairithromycin as it is contraindicated in pregancy.
Age as a factor in AB choice
Don’t use with Newborns Chloramphenicol, Sulfonamides (can’t glucuronidate) Don’t use in children Tetracyclines, Fluoroquinolones Don’t use during Pregnancy Tetracycline, Aminoglycosides, Clarithromycin, Fluoroquinolones, Chloramphenicol, Sulfonamides
In the elderly, adjust for reduced renal function. The half life of beta lactams, aminoglycosides and fluoroquinolones will be increased.
Genetic factors in AB choice
Agents that may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency
Sulfonamides (Trimethoprim/Sulfamethoxazole)
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:
aminoglycosides can lead to ototoxicity –> balance problems and nephrotoxicities
Important toxicities associated with antibiotics(not comprehensive)
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
Common drug hypersensitivities
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?
Aztreonam
Drug-Drug interactions
Rifampin induces drug metabolizing P450 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 synthesisAminoglycoside + 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 or excretion of the enzyme
Ampicillin-sulbactam, Amoxicillin-clavulanate, Piperacillin-tazobactam, Ticarcillin-clavulanate
Imipenem-cilastatin (blocks renal dehydropeptidase) Penicillin- probenecid (decrease renal excretion)
Drawbacks of using drugs in combination
1) Risk of toxicity from two agents
Vancomycin or Aminoglycosides each alone have some nephrotoxicity. If given together you get marked renal impairment.
2) Antagonism
Pneumococcal meningitis
Penicillin - 21% mortality
Penicillin + Tetracycline - 79% mortality
- Selection of microorganisms resistant to antibiotics
- Superinfection
- Extra cost
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?
Guidelines 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
