SITI SUPARTIDepart.of Pharmacology & Therapy

Faculty Of Medicine – Padjadjaran University

DRUGS USED IN THE TREATMENT OF TYPHOID

FEVER

CHLORAMPHENICOL

- Produced by streptomyces venezuelae- Could cause serious and fatal blood dyscrasias- Reserved for serious infection : e.G. Meningitis - typhoid fever

Mechanism of Action

* In eukaryotic cells : inhibit protein synthesis in bacteria* Penetrates bacterial cells by facillitated Diffusion* Inhibit mitochondrial protein synthesis in Mammalian erythropoetic cells seem to Be particularly sensitive to the drug

Antimicrobial actions :

* Is primarily bacteriostatic* Bactericidal to : h.Influenzae, n.Meningitidis Strep. Pneumonia* Gram-negative bacteria (>95%) are inhibited in vitro by 8.0 ug. / Ml or less : h.Influenzae,n.Meningitidis, n.Gonorrhoeae, salmonella typhi ,Brucella spp, bordetella pertussis* Most anaerobic bacteria including gram-positive cocci and Clostridium spp, and gram-negative rods incl. B.Fragilis, inhibited by 8.0 ug / ml. + Some aerobic gram-positive cocci incl. Strep pneumoniae* 95 % staph aureus are sensitive to four fold higher concent

Resistance to Chloramphenicol

- Increasing Clinical Importance

- Caused by : - Plasmid- The Presence of aspecific acetyl transferase

- Especially : Salmonella typhi

- Have been increased : Staphylococci ( Staph. aureus ) E. coli Pseudomonas

Absorption, Distribution, Fate and Excretion

Per Oral :Active drug (absorbed)Inactive drug (chloramphenicol palmitate/stearat used to prepareoral suspension) hydrolized, rapidly and almost completely by pancreatic lipase in duodenum

Chloramphenicol succinate (inactive drug) is used to preparesolution for parenteral use, hydrolized by esterases of theliver, kidneys, lung

Distribution :* in body fluids* Readily reaches csf in therapeutic concentration.

Elimination :* secreted into bile and milk* Readily traverses the placental barrier* Penetrates into the aquaeous humor After subconjuntival injection* Metabolism in liver* Excreted in urine

Therapeutic usesTherapy with chloramphenicol must be limited to infection for which the benefits of the drug out weigh the risks of potential toxicities. When other antimicrobial drugs are available that are equally effective and potentially less toxic chloramphenical, they should be used.( Kucer's bennet 1987, standiford, 1995 )

1. Typhoid fever and other types of systemic salmonella infection. Chloramphenicol is still important drug

2. Bacterial meningitis: cefotaxime, ceftriaxone, ceftizoxime have replaced chloramphenicol as initial therapy for meningitis when H.influenzae is suspected An alternative drug for meningitis caused by N.meningitidis and Strept. pneumoniae, after beta-lactam

3. Anaerobic Infection* Quite effective against most anaerobic bacteria including Bacteriodes spp.

* Chloramphenicol with penicillin for brain abscesses

* Chloramphenicol + penicillin or aminoglycoside for intraabdominal or pelvic abscesses

4. Rickettsial Diseases* DOC : tetracyclines* Severe illness : chloramphenicol

5. Brucellosis, Chloramphenicol is not as effective as tetra - cyclines. Relapses ussualy respond to retreatment

UNTOWARD EFFECTS

Hypersensitivity Reactions* Macular or vesicular skin rashes ( un common )* Fever (simultaneously or be the sole manifestation)* Angioedema (rare)* Jarisch-Herxheimer reaction (observed shortly after institution of chloramphenicol therapy for syphilis, brucellosis and typhoid fever.

Hematologic Toxicity* Bone marrow* a. Close related toxic effect :

1. Erythroid suppression of bone-marrow2. Anemia, leucopenia, thrombocytopenia

b. Idiosyncratic respons : (not close related) aplastic anemia to

fatal pancytopenia

* 70% blood dyscrasia : aplastic anemia* the remainder : hypoplastic anemia, agranulocytosis, thrombocytopenia, bone-marrow inhibition

" The risk of aplastic anemia does not contra indicate the use of chloramphenicol in situations in wich it is necessary ; however, it empha sizes the drug should never be employed in undefined situations or in diseases readily safety and effectively treatable with other antimicrobial agents".

Erythropoid suppression

* frequently results in hepatic disease ( most intense when ascites and jaundice are present* also in one third of patients with severe renal insufficiency

Toxic and irritative effects

* oral administration nausea, vomit, unpleasant taste, diarrhea, peritoneal irritation.

* blurring of vision, digital paraesthesia

* gray baby syndrom, 2 - 9 days after treatment is started. Has been reported in adult " a similar gray syndrome" 40% of patients are died . Recover no sequalae

DRUG INTERACTION

* Prolong the half-lives of drug :dicumarol, phenytoin, chlorpropamide, tolbutamid (Chloramphenicol irreversibly inhibit hepatic microsomal cytochrom P.450 enzymes). May occurred severe toxicity and death

* Other drugs may alter the elimination of chloramphenicol,chronic administration of phenobarbital, acute administration of rifampin shortens the half-life of the antibiotic.

THIAMPHENICOL• Indication: as same as chloramphenicol• Side effects:

– Bone marrow depression– Dose dependent– Reversible

• Reduced dose in renal failure• Bactericide to H.influenzae in sputum• In the treatment of urethritis gonorrhoica:

Single dose 2,5 gram per oral

THE TREATMENT OF TYPHOID FEVER

1. Drug of choice is chloramphenicol2. Could be treated by ampicilline3. Could be treated by thiamphenicolChloramphenicol could reduce the clinical symptoms faster than ampicillineBy ampicilline: relapse and carrier state is

rare