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Foundations of Medicine > Week 3 - Antibiotics - Cell Wall Inhibitors > Flashcards

Week 3 - Antibiotics - Cell Wall Inhibitors Flashcards

1
Q

Beta-Lactam characteristics

A

Include penicillin, cephalosporin, carbapenems, aztreonam

Bactericidal

All Beta-lactam antibiotics bind to the Penicillin Binding Proteins which are transpeptidases that catalyze the terminal reactions in bacterial cell wall synthesis.

Build-up of cell wall precursors leads to the activation of autolytic enzymes

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2
Q

Mechanism of Beta - Lactam antibiotics

A

to inhibit cross-linking of the peptidoglycan (murein) by transpeptidase.
Beta lactams occupy the D-alanyl-D-alanine substrate site of the transpeptidase

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3
Q

What do cell wall inhibitors do to cell?

Would swelling be more likely to occur when the cell is in a hypotonic or hypertonic solution?

A

Cell wall inhibitors weakens the cell wall, when water enters through osmosis, the cell bursts. Bactericidal

Hypotonic..

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4
Q

Penicillin Characteristics

A

Active against Gram positive organisms
Short half-life (30 min.) due to renal excretion and blood levels can be increased by simultaneous administration of probenecid, which impairs renal secretion of weak acids
Penicillin V (oral), Penicillin G (IV form),
Longer acting forms with delayed absorption like procaine, benzathine are available for intramuscular administration, but are associated with irritation and local pain
Hypersensitivity reaction- mild rash to anaphylaxis
Seizure, nausea, and diarrhea are common side effects

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5
Q

Penicillian V vs G?

A

V is oral

G is IV

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6
Q

Gram Pos organisms are killed by what class of antibiotics?

A

Penicillins

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7
Q

What are some adverse affects of Penicillin?

A

Hypersensitivity reaction- mild rash to anaphylaxis

Seizure, nausea, and diarrhea are common side effects

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8
Q

What are the IM forms of Penicillin?

A

Longer acting forms with delayed absorption like procaine, benzathine are available for intramuscular administration, but are associated with irritation and local pain

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9
Q

What is the 1st mechanism of resistance to Penicilin?

What bacterial are resistant?

A

Almost all Staphylococcal strains
and most Neisseria gonorrhea produce penicillinase

Penicillinase and Amidase inactivate penicillins

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10
Q

What are autolysins?

A

autolysins (e.g. murein hydrolase) that degrade existing peptidoglycans.

Isolates of some Staphylococcus, Streptococcus and Listeria have lost the ability to activate these enzymes and as a result are tolerant to pencillins.

The effect here is bacteriostatic rather than bactericidal

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11
Q

How would you propose to subvert penicillinase?

A

Inhibit the penicilinase

Change structure of penicillin so penicillinase cant bind

Use a non-penicillin antibiotic*

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12
Q

What are antistaphylococcal Penicillins?

A

Penicillinase-resistant penicillins with very narrow-spectrum

Nafcillin, Dicloxacillin (Methicillin-no longer used)

Same mechanism as penicillin but have larger R group so resistant to penicillinases

Methicillin Sensitive Staphylococci aureus (MSSA)

Can still result in hypersensitivity reactions

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13
Q

What is Nafcillin?

A

It is a penicillinase resistant penicillin

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14
Q

What are the four classes of Beta-lactamases?

A

Clavulanate

Sublactam

Tazobactam

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15
Q

What is clavulanate?

A

It is a class of Beta-lactamases

clavulanate inhibits Class A and D beta lactamases.

There are many beta-lactamase enzymes, some that prefer the penicillin structure (penicillinase), some that prefer the cephalosporin structure (cephalosporinase), and some that recognize both

Clavulanate is combined with penicillin. Clavulanate binds irreveresibly to penicillinase allowing penicillin to be an effective drug.

Clavulanate associated with diarrhea can be minimized by taking with food

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16
Q

Some penicillin are unable to penetrate some gram - neg membranes

A
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17
Q

What are aminopenicillins?

A

Wider spectrum penicillinase-susceptible drugs

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18
Q

Ampicillin and Amoxicillin

A

Ampicillin and Amoxicillin are more water soluble and can pass through porin channels

Same mechanism as penicillin and inactivated by many β-lactamases

Extends spectrum of penicillins to include Gram negative like H. influenza, E. coli, Listeria, Salmonella

Can still result in hypersensitivity reactions

Ampicillin can be combined with Sulbactam and Amoxicillin can be combined with Clavulanate

Ampicillin is associated with pseudomembranous colitis

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19
Q

Antipseudomonals

A

Wider spectrum penicillinase-susceptible drugs

20
Q

Ticarcillin and Piperacillin

A

Broad activity against Gram-negative bacilli including Pseudomonas

Same mechanism as penicillin and can become ineffective if penicillinase expressed (ticarcillin/clavulanate, piperacillin/tazobactam)

21
Q

Summary of Penicillins Table

A
22
Q

Penicillin Allergy Symptoms

How many people?

A

Symptoms include urticaria, angioedema, and anaphylaxis (which can be fatal)

Adult U.S. population, 3%–10% have experienced an immunoglobulin E (IgE)-mediated allergic response to penicillin

Only 5-10% of persons with a history of penicillin reaction have an allergic response when re-exposed and this decreases with time

0.05% of recipients have anaphylactic shock, treat with epinephrine

Penicillin skin testing can identify individuals at high risk of reaction

Cross-allergenicity between penicillins is hard to predict and in general should be assumed

23
Q

How does penicillin cause allergic reactions?

A

Penicillin and other beta lactams combine with your
proteins to form a ‘hapten-protein’ complex that stimulates
the immune system and results in production of specific
antibodies to this antigen

24
Q

Which drug to use if patient is allergic to penicillin?

A

Monobactum - Aztreonam

Monocyclic beta-lactams

Cell wall inhibitor and binds to penicillin binding protein

Gram-negative rods including Klebsiella, Pseudomonas, Serratia

25
Q

What are cephalosporins?

A

are less susceptible to penicillinases but can be inactivated by extended spectrum beta-lactamases

Beta-lactam drugs have same mechanism of action- inhibit cell wall synthesis by binding to penicillin binding proteins

Isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia

Bactericidal

May be cross-hypersensitivity with penicillin

Some available for oral use without food

Cephalosporins are primarily excreted by the kidney. Dosage may need to be altered in renal insufficiency.

26
Q

What are first generation cephalosporins?

A

1st gen- cefazolin, cephalexin, cefadroxil

Gram+ cocci

Surgical prophylaxis

Don’t use for CNS infections since don’t cross blood brain barrier

27
Q

What are 2nd generation cephalosporins?

A

2nd gen- cefoxitin, cefuroxime, cefotetan

More Gram- activity and weaker Gram+ activity

Use immediately prior to surgery to prevent infection

Don’t cross blood brain barrier well

Can inhibit Vitamin K production to prolong bleeding

Can cause a disulfiram-like reaction when coadminstered with ethanol

28
Q

What are 3rd generation cephalosporins?

A

3rd gen- ceftriaxone, cefotaxime, ceftazidime, cefdinir

Used for streptococci and more serious Gram- infections resistant to other Beta-lactams

Can cross blood brain barrier used for meningitis treatment

Ceftriaxone interacts with calcium- containing medications to form crystals that precipitate in the lungs and kidneys

Strong association with Clostridium difficile- associated diarrhea

29
Q

What are fourth generation cephalosporins?

A

4th gen- cefepime = cefazolin (1st gen) + ceftazidime (3rd gen)

**broadest spectrum- Gram+, Gram- including Pseudomonas **

30
Q

Given this spectrum (4th) would you predict that cefepime is used for

A Prophylactic therapy
B Empiric therapy
C Definitive therapy

A

B

31
Q

What are 5th generation cephalosporins?

A

5th gen- ceftaroline (new!)

Engineered to bind to penicillin-binding protein 2a present in MRSA that has low affinity for other beta-lactams. MRSA has changed conformation of the penicillin binding site.. this 5th gen cephalosporin is able to bind.

Used for skin and soft tissue infections (usually caused by stafforius)

32
Q

Carbapenems - Another class of beta lactams

A

imipenem/cilastatin, meropenem

Contain beta-lactam ring and bind to penicillin binding proteins

Low susceptibility to beta-lactamases

Broad spectrum but MRSA is resistant

Administered parenterally

Imipenem is administered with cilastatin to decrease inactivation of the drug by renal dehydropeptidase I and prevent formation of potentially toxic nephrotoxic metabolite.

Check dose with renal dysfunction to prevent seizures

Toxicity also associated with GI distress

33
Q

Characteristics of Beta Lactams…

A

Include penicillins, cephalosporin, and carbapenems

Bactericidal

All Beta-lactam antibiotics bind to the Penicillin Binding Proteins which are transpeptidases that catalyze the terminal reactions in bacterial cell wall synthesis (little benefit to giving >1) (so dont give two beta lactams to a pt at the same time)

Assume cross-allergenicity

Seizures can result from high doses of any of the Beta-lactams

34
Q

What are the cross resistance amongst Beta-lactams that can occur…

A

1st mechanism of resistance: Expression of Beta-lactamases

Almost all Staphylococci strains are now resistant

2nd mechanism of resistance:
Change in the structure of Penicillin Binding Proteins
(i.e. Methicillin-Resistant S. Aureus, pneumococci)

3rd mechanism of resistance:
Decrease in uptake of the drug

4th mechanism of resistance
Upregulation of efflux pumps

35
Q

What is Vancomycin?

What is its mechanism?

A

Vancomycin- is not a Beta-lactam and has different target in cell wall synthesis

Binds with high affinity to the D-alanyl-D-alanine terminus of the cell wall precursor unit, inhibiting release from the bactoprenol carrier, thus preventing peptidoglycan synthesis. Inhibits the polymerization or the transglycosylase reaction.

Bactericidal

Gram positive esp . MRSA, C difficile (very narrow)

Added to empiric treatment

Oral vancomycin is poorly absorbed

36
Q

What is the resistance method by Enterococci to Vancomycin?

A

Enterococci replace the -alanyl-D-alanine with a D-alanyl-D-lactate or D-alanyl-D-serine to prevent vancomycin binding.
Few staphylococci have learned vancomycin-resistance from Enterococci

Excreted by the kidney. Dosage adjusted in renal insufficiency

Toxicity Hypersensitivity reactions
Ototoxicity can occur with large or continued doses (>10d) in presence of renal damage
Nephrotoxicity

37
Q

What is bacitracin?

What is its mechanism of antibiotic?

A

Prevents the dephosphorylation of the bactoprenol carrier. This step is essential for regeneration of the bactoprenol carrier and continued elongation of the peptidoglycan cell wall.

Not a beta lactam antibiotic.

Inhibits dephosphorylation of the lipid carrier bactoprenol

Nephrotoxic when given systemically.

Rarely used except in topical ophthalmic and dermatologic preparations

Resistance rarely occurs

38
Q

What is Polymyxin B (triple antibiotic like neosporin)?

Mechanism?

A

Mechanism: Bind to phosphatidylethanolamine in the membrane creating holes ultimately leading to the release of cellular contents. Bacteriocidal

Spectrum: Multidrug resistant Gram negative including Pseudomonas aeruginosa (can infect just about any tissue type if defenses are weakened and in hospitalized patients with cancer, cystic fibrosis, and burns the fatality rate is near 50 percent.)

Side effects: Nephrotoxicity

Resistance:
Infrequent and slow to develop
Cross resistance does not develop
with any other presently used antibiotics

39
Q

What is Daptomycin?

What is its mechanism?

A

Daptomycin- Binds to the cell membrane of gram-positive bacteria leading to depolarization of membrane and cell death

Bactericidal

Used for the treatment of Gram-positive organisms (MRSA)

Resistance: addition of a positively charged lysine to cell surface which repels the positively charged drug and no cross-resistance

40
Q

Summary Table..

A
41
Q

30-year old patient presents with cough, runny nose, and sore throat. Which of the following treatments is most appropriate

Treatment with penicillin VK
Treatment with penicillin G
Treatment with amoxicillin
No treatment since the infection is most likely viral

A

No treatment since the infection is most likely viral

Cough* this is key.. cough is most likely viral…

If looks bacterial do rapid strep. Then if rapid strep is neg, and pt is child*, then culture it.

42
Q

An 8 year old boy with cystic fibrosis comes to the emergency department. He is extremely lethargic, is having difficulty breathing and is diagnosed with pneumonia. A gram negative rod is isolated from his sputum culture. You start immediate empiric drug therapy including a penicillin. Which of the following would you choose:

Cefazolin

Nafcillin

Penicillin G

Penicillin V

Piperacillin

What drug could you use if the patient has previous exhibited a penicillin allergy?

A

Piperacillin

All others don’t have a gram neg spectrum..

IF penicillin allergy - use aztreonam

43
Q

A 36 year old female is diagnosed with a serious central nervous system infection of bacterial meningitis. You start immediate therapy with a drug that you know penetrates the central nervous system. Which of the following drugs is the best choice

Cefazolin

Cefuroxime

Ceftriaxone

A

Ceftriaxone - first two aren’t good with CSF

44
Q

Which of the following drugs could be prescribed for a skin infection caused by methicillin-resistant Staphylococcus aureus (MRSA)?

A. Cefazolin
B. Ceftriaxone
C. Cefepime
D. Ceftaroline (5th gen.)

A

D

What other drugs?

45
Q

Which of the following drugs is susceptible to beta-lactamases produced by staphylococci?

Amoxicillin
Imipenem
Piperacillin/tazobactam
Dicloxacillin
Vancomycin

A

Amoxicillin

46
Q

Which of the following drugs would you add to your treatment with amoxicillin to decrease degradation of amoxicillin by beta-lactamases?

A. Aztreonam
B. Probenicid
C. Clavulanate
D. Nafcillin
E. Cilastatin

A

B. Probenicid

47
Q

What endotoxin is very stable? and not susceptible to autoclaving?

A

LPS

Sterilization- LPS (endotoxin) is very stable. Autoclaving is not sufficient for inactivation needs to be heated to 250°C

For sterilization including endospores, autoclaving and UV light are the most effective approach.
The high heat denatures proteins and disrupts membranes. To kill spores, at dry heat at 160C it takes 2hr vs. equivalent killing was seen after 5 min. at 121C in an autoclave.
Steam facilitates better penetration and more efficient heat transfer to promote killing of the organism.

Unlike sterilization, chemical disinfection is generally not sporicidal. Bleach is more effective than benzalkonium chloride which is a (quaternary ammonium compound).

Foundations of Medicine (42 decks)

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