Week 3 - Antibiotics - Cell Wall Inhibitors

Question 1

Beta-Lactam characteristics

Answer 1

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

Question 2

Mechanism of Beta - Lactam antibiotics

Answer 2

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

Question 3

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?

Answer 3

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

Hypotonic..

Question 4

Penicillin Characteristics

Answer 4

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

Question 5

Penicillian V vs G?

Answer 5

V is oral

G is IV

Question 6

Gram Pos organisms are killed by what class of antibiotics?

Answer 6

Penicillins

Question 7

What are some adverse affects of Penicillin?

Answer 7

Hypersensitivity reaction- mild rash to anaphylaxis

Seizure, nausea, and diarrhea are common side effects

Question 8

What are the IM forms of Penicillin?

Answer 8

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

Question 9

What is the 1st mechanism of resistance to Penicilin?

What bacterial are resistant?

Answer 9

Almost all Staphylococcal strains
and most Neisseria gonorrhea produce penicillinase

Penicillinase and Amidase inactivate penicillins

Question 10

What are autolysins?

Answer 10

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

Question 11

How would you propose to subvert penicillinase?

Answer 11

Inhibit the penicilinase

Change structure of penicillin so penicillinase cant bind

Use a non-penicillin antibiotic*

Question 12

What are antistaphylococcal Penicillins?

Answer 12

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

Question 13

What is Nafcillin?

Answer 13

It is a penicillinase resistant penicillin

Question 14

What are the four classes of Beta-lactamases?

Answer 14

Clavulanate

Sublactam

Tazobactam

Question 15

What is clavulanate?

Answer 15

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

Question 16

Some penicillin are unable to penetrate some gram - neg membranes

Answer 16

Question 17

What are aminopenicillins?

Answer 17

Wider spectrum penicillinase-susceptible drugs

Question 18

Ampicillin and Amoxicillin

Answer 18

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

Question 19

Antipseudomonals

Answer 19

Wider spectrum penicillinase-susceptible drugs

Question 20

Ticarcillin and Piperacillin

Answer 20

Broad activity against Gram-negative bacilli including Pseudomonas

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

Question 21

Summary of Penicillins Table

Answer 21

Question 22

Penicillin Allergy Symptoms

How many people?

Answer 22

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

Question 23

How does penicillin cause allergic reactions?

Answer 23

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

Question 24

Which drug to use if patient is allergic to penicillin?

Answer 24

Monobactum - Aztreonam

Monocyclic beta-lactams

Cell wall inhibitor and binds to penicillin binding protein

Gram-negative rods including Klebsiella, Pseudomonas, Serratia

Question 25

What are cephalosporins?

Answer 25

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.

Question 26

What are first generation cephalosporins?

Answer 26

1st gen- cefazolin, cephalexin, cefadroxil **Gram+ cocci** Surgical prophylaxis Don’t use for CNS infections since don’t cross blood brain barrier

Question 27

What are 2nd generation cephalosporins?

Answer 27

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

Question 28

What are 3rd generation cephalosporins?

Answer 28

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

Question 29

What are fourth generation cephalosporins?

Answer 29

4th gen- cefepime = cefazolin (1st gen) + ceftazidime (3rd gen) **broadest spectrum- Gram+, Gram- including Pseudomonas **

Question 30

Given this spectrum (4th) would you predict that cefepime is used for A Prophylactic therapy B Empiric therapy C Definitive therapy

Answer 30

B

Question 31

What are 5th generation cephalosporins?

Answer 31

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)

Question 32

Carbapenems - Another class of beta lactams

Answer 32

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

Question 33

Characteristics of Beta Lactams...

Answer 33

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

Question 34

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

Answer 34

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

Question 35

What is Vancomycin? What is its mechanism?

Answer 35

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

Question 36

What is the resistance method by Enterococci to Vancomycin?

Answer 36

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 ## Footnote 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

Question 37

What is bacitracin? What is its mechanism of antibiotic?

Answer 37

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

Question 38

What is Polymyxin B (triple antibiotic like neosporin)? Mechanism?

Answer 38

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

Question 39

What is Daptomycin? What is its mechanism?

Answer 39

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

Question 40

Summary Table..

Answer 40

Question 41

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

Answer 41

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.

Question 42

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?

Answer 42

Piperacillin All others don't have a gram neg spectrum.. IF penicillin allergy - use aztreonam

Question 43

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

Answer 43

Ceftriaxone - first two aren't good with CSF

Question 44

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.)

Answer 44

D What other drugs?

Question 45

Which of the following drugs is susceptible to beta-lactamases produced by staphylococci? Amoxicillin Imipenem Piperacillin/tazobactam Dicloxacillin Vancomycin

Answer 45

Amoxicillin

Question 46

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

Answer 46

B. Probenicid

Question 47

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

Answer 47

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).