11 Chloramphenicol. Polymixins. Antifolate drugs

Question 1

What is the mechanism of action of chloramphenicol?

Answer 1

• Protein synthesis inhibition in bacteria:
  
  • They bind reversibly the 50S ribosomal subunit è inhibition of the activity of peptidyl transferase
• Bacteriostatic drugs

Question 2

What is the antibacterial spectrum of Chloramphenicol and it’s resistance?

Answer 2

Broad-spectrum

• Gram (+) and (-) bacteria
• Anaerobes, Rickettsia, Chlamydia and Spirochetes

Resistance:

• Enzymatic inactivation of chloramphenicol
• Reduced permeability into the organism
• Ribosomal binding site alterations

Question 3

What is the indication of Chloramphenicol?

Answer 3

• Meningitis in case of b-lactam allergy
• Severe rickettsiosis in children

Question 4

What are the pharmacokinetics of chloramphenicol?

Answer 4

• IV administration:
  
  • 4x/day
• Excellent absorption and tissue penetration (including CSF)
  
  • Very lipid soluble, thus enters CNS
• Metabolized by hepatic glucuronidation
  
  • Dose reductions are needed in liver dysfunction and in neonates
  • Inhibition of cytochrome P450
• Eliminated in the urine

Question 5

What are the side effects of chloramphenicol?

Answer 5

• Dose-dependent bone marrow suppression common
  
  • Aplastic anemia is rare (1 in 20’000)
    
    • It can also be dose-independent idiosyncratic
• “Gray baby” syndrome in neonates
  
  • Due to low ability to conjugate with glucoronate (low glucuronosyl transferase in babies) and underdeveloped renal function
    
    • Reduced ability to excrete the drug ==> accumulation of the drug ==> dysfunction of mitochondrial ribosomes
      
      • Poor feeding
      • Depressed breathing
      • Cardiovascular collapse
      • Cyanosis (“gray baby”)
      • –> Death

Drug interaction:

• Inhibition of CYP450 ==> blocked metabolism of warfarin and phenytoin

Question 6

What are polymixins?

Types?

Mechanism of action?

…?

Answer 6

• It is a mixture of polypeptide sulfates (B and E)
• Concentration-dependent bactericidal agents
• Mechanism of action: bind the plasma membrane and alter permeability
• Spectrum:
  
  • Gram (-) bacteria (e.g. Pseudomonas Aeruginosa, E. Coli, Klebsiella pneumoniae, Acinetobacter spp, Enterobacter spp)
  • No effect: B. Fragilis, Proteus spp, gram (+)
• Kinetics:
  
  • Only parenteral
  • Poor distribution
  • No entering into CNS
  • Topical usage (drops)
• Adverse effects: Nephrotoxic and neurotoxic (may cause NMJ block)
• Indication: P. Aeruginosa and other gram (-), it is active against nothing else!!!

Polymyxin B:

• Parenteral, ophthalmic and otic topical preparations

Polymyxin E (Colistin):

• Drugs:
  
  • Colistin
  • Cholistimetate (prodrug)
• Indication:
  
  • P. Aeruginoa or other gram (-)
  • In the pulmonology (cystic fibrosis)
  • Aerosol or IV
• Adverse effects:
  
  • Risk of nephrotoxicity and neurotoxicity

Question 7

Which are the types of sulfonamides?

Answer 7

Oral absorbable agents:

• Drugs:
  
  • Short-acting
  • Medium-acting (important in combination):
    
    • Sulfamethoxazole
    • Sulfadiazine
  • Long-acting (important only in malaria treatment)
    
    • Sulfadoxine
• Clinical use:
  
  • Alone very rarely
  • Perhaps for UTI

Oral non-absorbable agents:

• Sulfasalazine
  
  • Used in ulcerative colitis

Topical agents:

• Sulfacetamine
  
  • Used in conjunctivitis, trachoma
• Silver sulfadiazine
  
  • Used in burn wounds
• Sulfadimidine
  
  • Used as an ophthalmological cream

Question 8

What are the features of sulfonamides?

Mechanism?

Spectrum?

…

Answer 8

Mechanism of action:

• They are synthetic analogs of PABA, thus they compete with it for the bacterial enzyme, dihydropteroate synthetase ==> inhibition of the synthesis of bacterial dihydropteroic acid
• Bacteriostatic

Spectrum:

• Gram (+) and (-)
• Nocardia
• Chlamydia trachomatis
• Some protozoons
• Some enteric bacteria

Resistance:

• Overproduction of PABA
• Production of folic acid-synthetizing enzyme with lower affinity for sulfonamides
• Reduced permeability

Pharmacokinetics:

• Good absorption from the GI tract
• Wide distribution (including CSF, placenta and fetus)
• High protein binding
• Metabolism in the liver (acetylation, glucuronidation)
• Excretion with the urine (in part unchanged)
  
  • Glomerular filtration
  • Tubular secretion

Adverse effects:

• Allergic reactions (Skin rashes, fever, Stevens-Johnson syndrome, …)
  
  • All sulfonamide derivatives can be cross-allergenic, besides antibiotics e.g. carbonic anhydrase inhibitors, thiazide diuretics, furosemide, sulfonylurea antidiabetic agents, …
• Photosensitivity
• GI effects (nausea, vomiting, pain, diarrhea)
• Nephrotoxicity
  
  • Precipitation in urine ==> crystalluria, hematuria
    
    • To avoid it: adequate hydration (more than 1 liter/day),
• Hematotoxicity in G6P deficiency
  
  • Hemolytic anemia
  • Aplastic anemia
  • Granulocytopenia
  • Thrombocytopenia
• In newborns: competition with bilirubin ® risk of Kernicterus

Question 9

What is the mechanism of Trimethoprim?

Answer 9

It inhibits dihydrofolate reductase ==> reduced availability of tetrahydrofolate cofactor required for purine, pyrimidine and amino acid synthesis

Question 10

What are the features of tr**imethoprim as monotherapy?

Answer 10

Spectrum:

• Similar to sulfamethoxazole
• Used in monotherapy
  
  • Rapid development of resistance

Pharmacokinetics:

• Similar to sufamethoxazole
  
  • Better penetration into the brain
  • Very high concentration in prostatic fluid and in vaginal fluid (high antibacterial activity there)

Question 11

Whatre are the features of trimethoprim + sulfamethoxazol (cotrimoxazole)?

Answer 11

• The combination is often bactericidal

Spectrum:

• Gram (+) like Staph, Listeria, Nocardia
• Gram (-) like Enterobacterias, E. Coli, Shigella, Salmonella, H. Influenza, Chlamydia, Yersinia
• Protozoons like Pneumocystis jiroveci, Toxoplasma, Plasmodium
• No action against:
  
  • Rickettsia
  • Treponema
  • Mycobacterium
  • Tuberculosis
  • Anaerobes

Clinical use:

• Pneumocystitis jiroveci (high dose– 5-6 tabs/day), also for prophylaxis
• Toxoplasmosis, Nocardia, Burkholderia, Stenotrophomonas, Serratia (even multiresistant strains might be sensitive)
• Respiratory tract pathogens, Shigella enteritis, some salmonella infections, travelers’ diarrhea
• Low UTIs (recidiva prophylaxis)

Administration:

• Both oral and parenteral (infusion)

Contraindications:

• Allergy
• Acute hepatitis
• Severe kidney failure
• G6P deficiency
• Newborn babies, preterm babies until 1 year
• Pregnancy, nursing
• Cautiously has to be given in case of risk of folic acid deficiency (e.g. Antiepileptic treatment, elder people, alcoholics)

Question 12

What are the features of pyrimethamine + sulfadiazine/sulfadoxine?

Answer 12

Indications:

• Leishmaniasis
• Toxoplasmosis
• Plasmodium Falciparum