C.11. Chloramphenicol. Polymyxins. Antifolate drugs. Flashcards
mechanism of action of Chloramphenicol
binds reversibly to the 50s subunit of the bacterial ribosome–> inhibits peptide bond formation
bacteriostatic effect
which strains are highly susceptible to chloramphenicol (bactericidal)?
H. influenza
N. Meningitidis
Bacteroids
what happens in ‘Grey baby syndrome’?
↓ degradation of chloramphenicol cause of ↓ in the activity of glucuronic acid conjugation–> chloramphenicol accumulates in the body and blocks oxidative phosphorylation–> no ATP–> MOF
Symptoms of ‘Grey baby syndrome’
↓ RBC’s, cyanosis, cardiovascular collapse (infants))
what is the spectrum and clinical use of Chloramphenicol?
wide spectrum
limited systemic use–> toxic
topical antimicrobial agent (synthomycin)
empiric treatment for bacterial meningitis
backup drug against Rickettsia, B. fragilis, salmonella.
how do we give chloramphenicol?
oral/parenteral
is chloramphenicol an inhibitor of CYP450 enzymes?
yes
what type of metabolism occurs in chloramphenicol?
hepatic
chloramphenicol crosses the..
placenta and BBB
there are 2 possible mechanisms of resistance for chloramphenicol. what are they?
- Bacteria may express plasmid-encoded acetyltransferase –> inactivates the drug
- alteration of drug binding site
side effects of Chloramphenicol
- GI symptoms (dysbacteriosis), risk of candida superinfection
- dose-dependent bone marrow suppression (reversible)
- aplastic anemia (rare)
- ‘Grey baby syndrome’
what is Polymyxin E (Colistin) and what does it do?
Acts as a cationic detergent (disrupting bacterial cell membrane)
binds and inactivates endotoxins
*bactericidal effect
how do we give Polymyxin E (Colistin)?
topical/ parenteral
*systemic use–> severe side effects
side effects of polymyxin E?
Neurotoxicity (dizziness, ataxia, paraesthesia)
Nephrotoxicity (acute tubular necrosis)
what are the indications of Polymyxin E?
gram - organisms
superficial skin infections (topical)
highly resistant strains of pseudomonas and Acinetobacter
what is an antimetabolite?
a substance inhibiting cell growth by competing with, or substituting for, a natural substrate in an enzymatic process
what is a sequential blockade? give an example of an AB
inhibiting sequential steps in a pathway of bacterial metabolism, by 2 different drugs that have a combined synergistic effect.
Trimethoprim+ Sulfamethoxazole –> bactericidal `
drugs that can cause sulfonamide hypersensitivity (non-AB)
loop, thiazide and CAI diuretics
sulfonylurea
Celecoxib (selective COX-2 inhibitor)
Probenecid
what is the presentation of Sulfonamide hypersensitivity?
skin rash (potentially painful)
fever
urticaria
steven johnson syn.
what are Sulfonamides
competitive inhibitors of dihydropteroate synthase
bacteriostatic effect
weak acid
give examples of Sulfonamides
Sulfisoxazole (short-acting)
Sulfamethoxazole (intermediate)
Sulfadoxine (long-acting)
what is Trimethoprim
selective inhibitor of bacterial dihydrofolate reductase
bacteriostatic effect
weak base
*used only in combination with sulfonamides
TMP-SMX= Cotrimoxazole
when do we give Proguanil?
Malaria prophylaxis
with atovaquone
how do we give Proguanil?
orally
side effects of Trimethoprim
- bone marrow suppression (rarely seen)
2. Enterocolitis
when do we give Pyrimethamine/Sulfadiazine?
toxoplasmosis
treatment and prophylaxis in HIV patients (CD4<100/µL)
what is the T1/2 of Trimethoprim?
10-12 h’
what do sulfonamides displace when binding to plasma proteins?
bilirubin
warfarin
methotrexate
what type of metabolism do sulfonamides have and how are they excreted?
hepatic metabolism.
they are excreted in the urine intact or metabolized.
where does Trimethoprim reach its highest concentration?
in prostatic and vaginal fluids
indications for TMP-SMX
- gram-positive bacteria (including some MRSA, staph, strep, Nocardia)
- gram-negative bacteria (E.coli, salmonella, shigella, H,influenzae)
- Pneumocystis jirovecii treatment and prophylaxis for HIV patients (CD4<200/µL)
- UTI, recurrent
what is silver-sulfadiazine used for?
burn infections, topical
what is Sulfasalazine used for?
Rheumatoid arthritis and ulcerative colitis (oral)
adverse effects of sulphonamides
- sulfonamide hypersensitivity
- GI symptoms
- bone marrow suppression
- acute hemolysis in G6PD deficient patients
- Nephrotoxicity (crystalluria)
- photosensitivity
- teratogenic (neural tube defects)
mechanism of resistance of Trimethoprim
production of dihydrofolate reductase that has a reduced affinity for the drug
mechanism of resistance of sulfonamides
- ↓ intracellular accumulation of the drug
- ↑ production of PABA by bacteria
- ↓ sensitivity of bacterial Dihydropteroate synthase to the drug
