C.11. Chloramphenicol. Polymyxins. Antifolate drugs.

Question 1

mechanism of action of Chloramphenicol

Answer 1

binds reversibly to the 50s subunit of the bacterial ribosome–> inhibits peptide bond formation
bacteriostatic effect

Question 2

which strains are highly susceptible to chloramphenicol (bactericidal)?

Answer 2

H. influenza
N. Meningitidis
Bacteroids

Question 3

what happens in ‘Grey baby syndrome’?

Answer 3

↓ degradation of chloramphenicol cause of ↓ in the activity of glucuronic acid conjugation–> chloramphenicol accumulates in the body and blocks oxidative phosphorylation–> no ATP–> MOF

Question 4

Symptoms of ‘Grey baby syndrome’

Answer 4

↓ RBC’s, cyanosis, cardiovascular collapse (infants))

Question 5

what is the spectrum and clinical use of Chloramphenicol?

Answer 5

wide spectrum
limited systemic use–> toxic
topical antimicrobial agent (synthomycin)
empiric treatment for bacterial meningitis
backup drug against Rickettsia, B. fragilis, salmonella.

Question 6

how do we give chloramphenicol?

Answer 6

oral/parenteral

Question 7

is chloramphenicol an inhibitor of CYP450 enzymes?

Answer 7

yes

Question 8

what type of metabolism occurs in chloramphenicol?

Answer 8

hepatic

Question 9

chloramphenicol crosses the..

Answer 9

placenta and BBB

Question 10

there are 2 possible mechanisms of resistance for chloramphenicol. what are they?

Answer 10

1. Bacteria may express plasmid-encoded acetyltransferase –> inactivates the drug
2. alteration of drug binding site

Question 11

side effects of Chloramphenicol

Answer 11

1. GI symptoms (dysbacteriosis), risk of candida superinfection
2. dose-dependent bone marrow suppression (reversible)
3. aplastic anemia (rare)
4. ‘Grey baby syndrome’

Question 12

what is Polymyxin E (Colistin) and what does it do?

Answer 12

Acts as a cationic detergent (disrupting bacterial cell membrane)
binds and inactivates endotoxins
*bactericidal effect

Question 13

how do we give Polymyxin E (Colistin)?

Answer 13

topical/ parenteral

*systemic use–> severe side effects

Question 14

side effects of polymyxin E?

Answer 14

Neurotoxicity (dizziness, ataxia, paraesthesia)

Nephrotoxicity (acute tubular necrosis)

Question 15

what are the indications of Polymyxin E?

Answer 15

gram - organisms
superficial skin infections (topical)
highly resistant strains of pseudomonas and Acinetobacter

Question 16

what is an antimetabolite?

Answer 16

a substance inhibiting cell growth by competing with, or substituting for, a natural substrate in an enzymatic process

Question 17

what is a sequential blockade? give an example of an AB

Answer 17

inhibiting sequential steps in a pathway of bacterial metabolism, by 2 different drugs that have a combined synergistic effect.
Trimethoprim+ Sulfamethoxazole –> bactericidal `

Question 18

drugs that can cause sulfonamide hypersensitivity (non-AB)

Answer 18

loop, thiazide and CAI diuretics
sulfonylurea
Celecoxib (selective COX-2 inhibitor)
Probenecid

Question 19

what is the presentation of Sulfonamide hypersensitivity?

Answer 19

skin rash (potentially painful)
fever
urticaria
steven johnson syn.

Question 20

what are Sulfonamides

Answer 20

competitive inhibitors of dihydropteroate synthase
bacteriostatic effect
weak acid

Question 21

give examples of Sulfonamides

Answer 21

Sulfisoxazole (short-acting)
Sulfamethoxazole (intermediate)
Sulfadoxine (long-acting)

Question 22

what is Trimethoprim

Answer 22

selective inhibitor of bacterial dihydrofolate reductase
bacteriostatic effect
weak base

*used only in combination with sulfonamides
TMP-SMX= Cotrimoxazole

Question 23

when do we give Proguanil?

Answer 23

Malaria prophylaxis

with atovaquone

Question 24

how do we give Proguanil?

Answer 24

orally

Question 25

side effects of Trimethoprim

Answer 25

1. bone marrow suppression (rarely seen) | 2. Enterocolitis

Question 26

when do we give Pyrimethamine/Sulfadiazine?

Answer 26

toxoplasmosis | treatment and prophylaxis in HIV patients (CD4<100/µL)

Question 27

what is the T1/2 of Trimethoprim?

Answer 27

10-12 h'

Question 28

what do sulfonamides displace when binding to plasma proteins?

Answer 28

bilirubin warfarin methotrexate

Question 29

what type of metabolism do sulfonamides have and how are they excreted?

Answer 29

hepatic metabolism. | they are excreted in the urine intact or metabolized.

Question 30

where does Trimethoprim reach its highest concentration?

Answer 30

in prostatic and vaginal fluids

Question 31

indications for TMP-SMX

Answer 31

1. gram-positive bacteria (including some MRSA, staph, strep, Nocardia) 2. gram-negative bacteria (E.coli, salmonella, shigella, H,influenzae) 3. Pneumocystis jirovecii treatment and prophylaxis for HIV patients (CD4<200/µL) 4. UTI, recurrent

Question 32

what is silver-sulfadiazine used for?

Answer 32

burn infections, topical

Question 33

what is Sulfasalazine used for?

Answer 33

Rheumatoid arthritis and ulcerative colitis (oral)

Question 34

adverse effects of sulphonamides

Answer 34

1. sulfonamide hypersensitivity 2. GI symptoms 3. bone marrow suppression 4. acute hemolysis in G6PD deficient patients 5. Nephrotoxicity (crystalluria) 6. photosensitivity 7. teratogenic (neural tube defects)

Question 35

mechanism of resistance of Trimethoprim

Answer 35

production of dihydrofolate reductase that has a reduced affinity for the drug

Question 36

mechanism of resistance of sulfonamides

Answer 36

1. ↓ intracellular accumulation of the drug 2. ↑ production of PABA by bacteria 3. ↓ sensitivity of bacterial Dihydropteroate synthase to the drug