Other CWIs and Sulfonamides Dr. Roane

Question 1

Bacitracin - Non beta-lactam

Answer 1

-cyclic polypeptide produced by Bacillus subtilis

-effective topically against a narrow spectrum gram + bacteria

-high rate of allergic reactions (rash to anaphylaxis)

Question 2

What is the MOA of Bacitracin?

Answer 2

It blocks the dephosphorylation of C55-isoprenyl pyrophosphate (bactoprenol, undecaprenyl pyrophosphate)

-> It can not be recycled (can´t switch sides of the inner membrane)

Question 3

Function of C55-isoprenyl pyrophosphate
(bactoprenol, undecaprenyl pyrophosphate)

Answer 3

It carries Peptidoglycans from the cytoplasm into the periplasm to become part of the outer cell wall

Question 4

What are the different MOA of drugs blocking cell wall synthesis?

Answer 4

1. Fosfomycin (UTI) -> blocking the conversion of NAM to NAG in the cytoplasm
2. Cycloserine -> conversion of L-Alanin to D-Alanin and formation of building D-Ala to D-Ala
3. Bacitracin -> blocking recycling of Bactoprenol
4. Vancomycin -> blocking the Transglycolase (joining of sugar molecules)
5. ß-lactams -> blocks formation of lattice network (blocking Transpeptidase)

Question 5

Difference between Vancomycin and ß-lactams

Answer 5

-VNC binds to D-Ala which is the substrate and thereby inhibits the enzyme: Transglycolase and also interferes with the Transpeptidase

-ß-lactams block Transpeptidases

Question 6

How do bacteria develop resistance against Vancomycin?

Answer 6

8 mutations on the binding site-> substitution of D-Ala to Serine or D-lactate

Question 7

Spectrum of Vancomycin

Answer 7

Gram (+) cocci
Staph aureus (MRSA)
Staph epidermidis and more

Side effects: Nephro and Otistoxicity
Redman syndrome

Question 8

What makes newer Vancomycin-like drugs different?

Answer 8

The structure is vancomycin-like, but they have a long lipid tail and the half-life is longer

-Telavancin (Vibativ), Oritavancin (Orbactiv), Dalbavancin (Dalvance)

Question 9

MOA of Polymyxin B

Answer 9

-Hydrophilic (binds water) and Hydrophobic -lipophilic tail (binds lipid of the cell wall; binds Lipid A of LPS in gram (-))
-Not absorbed PO -> Injectable and topical
-fairly toxic to kidney (nephrotoxic)

Question 10

Colistin (Polymyxin E)

Answer 10

-Structure like Polymyxin B
Binds to LPS (grm -) and creates a hole in the cell
membrane
-Used in the treatment of resistant acinetobacter
infections
-may be used for K. pneumoniae, P. aeruginosa, and NDM-1

Question 11

MOA of Daptomycin (Cubicin)

Answer 11

-Lipopeptide
-Disrupts the double-layered cell membrane (not the wall -> depolarization -> cell death without cell lysis

Question 12

What are toxins released by Staph aureus upon cell lysis?

Answer 12

-Alpha toxin (a-hemolysin) - form pores -> Apoptosis (low concentration), necrosis (high)
-Beta toxin (sphingomyelinase) - damage to many cell types

-Delta toxin – (d-hemolysin) pore-former, immunogenic
-Exfoliatin binds desmosomes in the skin -> can cause skin and soft tissue damage SSTI

-Toxic Shock Syndrome Toxin

Question 13

What type of drugs are Sulfonamides and Trimethoprim?

Answer 13

Metabolism inhibitor

Question 14

MOA of Sulfonamides

Answer 14

-They mimic Para-aminobenzoic acid in bacteria (PABA)

-PABA is converted to THF-C tetrahydrofolate (needed for Protein synthesis, and DNA synthesis) in bacteria

-Sulfonamides blocks Dihydropteroate synthase (first step of conversion)

FOLIC ACID Metabolism BLOCKED

Question 15

What is the MOA of Trimethoprim?

Answer 15

-inhibits the next step of conversion
-blocks DHR = dihydrofolate reductase

Sulfonamides and Trimethoprim = SYNERGY

FOLIC ACID Metabolism BLOCKED

Question 16

How can bacteria counteract Sulfonamides?

Answer 16

-Bacteria that can use preformed folic acid are not
affected

-Increased production of PABA can counteract Sulfonamides

-not affected by mammals bc they use preformed folic acid

Question 17

How can Sulfonamides cause Hypersensitivity?

Answer 17

-Absorption from the GI, vaginally or through damaged skin to the bloodstream

-can cross BBB

immunologic response, skin blisters (mild), wide-spread blisters (Stevens-Johnson syndrome - SJS (life-threatening)

Question 18

Side effects of Sulfonamides?

Answer 18

-Renal damage
-Photosensitivity - sunburn
-could cause folate-related problems in folate-deficient pts -> blood dyscrasias bc of the absence of starting material to make new blood cells

-adverse rxns in AIDS patients

Question 19

How are Sulfonamides metabolized?

Answer 19

-Phase II acetylation in the liver, to a limited extent
-Metabolites are inactive against bacteria but retain toxicity

-mostly excreted unchanged but can form crystals in the urine -> it damages epithelium, obstruct urine flow, kidney stones

Question 20

What is the most commonly used Sulfonamide?

Answer 20

-Sulfamethoxazole/Trimethoprim
-TMP-SMX (Septra, Bactrim, Co-trimoxazole)

-covers a number of bacteria including Staph. Infections and some
GNB

Question 21

What is the indication of Sulfisoxazole (Gantrisin)

Answer 21

-with phenazopyridine (analgesic) against bladder and urinary tract infections - colors urine bright orange

-Combined with erythromycin ethyl succinate (Pediazole) it treats otitis media

Question 22

Sulfadiazine

Answer 22

in vitro: gram (+) and gram (-) bacteria
-Enterobacter sp., Escherichia coli, Haemophilus, Klebsiella sp., Neisseria, Staph aureus

Drug of choice for Toxoplasma gondii: Sulfadiazine with pyrimethamine used for malaria

Question 23

Silver sulfadiazine (Silvadene)

Answer 23

-Bacteriostasis in nearly all pathogenic bacteria and fungi
-Topical: It is absorbed through the skin
(hypersensitivity issues)

-Preventing infections after burns

-BUT silver toxicity accumulates in the skin (Argyia)

Question 24

Drug interactions of Sulfonamides

Answer 24

-inhibition of metabolism
-displacement from Albumin

-oral anticoagulants, sulfonylurea hypoglycemic agents, hydantoin anticonvulsants

Question 25

Mechanism of resistance for Sulfonamides

Answer 25

-Lower affinity of sulfonamides to dihydropteroate synthase (first enzyme in folate metabolism)

-decreased bacterial permeability or active efflux

-different pathways used for metabolite synthesis

-increased production of metabolite (PABA) or drug antagonist

Question 26

What are some side effects of Sulfonamides affecting the skin?

Answer 26

• erythema multiforme

-> Skin blister
-> widespread: Stevens-Johnson syndrome - SJS

Question 27

What is a thrush?

Answer 27

-Overgrowth of yeast causing candidiasis in the mouth

Question 28

Which drug causes Red man syndrome?

Answer 28

Vancomycin