CHLORAMPHENICOL

PROF DR SHAH MURAD shahhmurad65@gmail.com 0314-2243415

 Broad spectrum antibiotic usually bacteriostatic sometimes bactericidal against certain species of microorganisms, when given in high concentration Chloramphenicol interferes with the protein synthesis.

Mechanism of Action
Chloramphenicol inhibits protein synthesis in bacteria, to a lesser extent, in eukaryotic cells. Drug penetrates bacterial cells by facilitated diffusion Primarily acts by binding reversibly to 50S ribosomal sub-unit. (competes macrolides and clindamycin) Prevents binding of amino-acids containing end of amino-acyl tRNA to receptor site on 50S ribosomal sub-unit. The interaction between peptidyl transferase and its amino acid substrate can not occur and peptide bond

 Eukaryotic erythropoietic cells are sensitive to Chloramphenicol because it can inhibit mitochondrial protein synthesis (70S). (cytoplasmic is 80S)

Spectrum Of activity
Bacteriostatic wide spectrum antibiotic Bactericidal for certain sp. E.g., H. Influenzae >>>>>>

 H. Influenzae causes bacteremia, pneumonia, and acute bacterial meningitis. On occasion, it causes cellulitis, osteomyelitis, epiglottitis, and infectious arthritis otitis media, eye infections (conjunctivitis), and sinusitis in children associated with pneumonia.

 Meningeococcal infections, like N. meningitidis, Meningococcemia (dissiminated intravascular coagulation >>>>>> causing necrotic tissue damage)

 Strp. pneumoniae

 More than 95% of the following Gramve bacteria are inhibited: >>>>>>> H. influenzae, N. meningitidis, N. gonorrhoeae, Brucella, Bordetella pertussis.

Spectrum
Anaerobic bacteria including G-ve cocci, clostridium and G-ve rods including B. Fragilis. Active against Mycoplasma, chlamydia and rickettsiae.

 E. Coli, Klebsiella pneumoniae ( most strains) Proteus mirabilis and indole-positive Proteus. (50%) Vibrio Cholera Shigella and salmonella resistant to multiple drugs including Chloramphenicol are on the rise Of special concern is increasing prevalence of multiple drug-resistant strains of salmonella serotype typhi

Resistance:
Resistance develops due to enzymatic deactivation of chloramphenicol by a plasmidencoded acetyl-transferase

Pharmacokinetics
Dose: 50 100mg/kg/d Available in oral -- Chloramphenicol, Chloramphenicol palmitate.. >>>> Absorbed rapidly from GIT. Parenteral Chloramphenicol succinate.

 Distribution:
Well distributed in body fluids, CSF etc. May accumulate in brain tissue Present in bile, milk and crosses placental barrier Penetrates aqueous humor after sub-conjunctival injection

Elimination
Elimination is primarily through the liver, it is converted to inactive glucuronide, with this metabolite as well as chloramphenicol itself is excreted in urine by filtration secretion. Dose need not to be adjusted in renal patients BUT checked in patients with impaired liver functions

Therapeutic Uses
Therapy with chloramphenicol must be limited to infections for which the benefits of drug-use out weigh the risks of potential toxicity

When other antibiotic are available which are less toxic and equally effective, then they should be preferred.

 Typhoid: (and other salmonella infections)

 It is an important drug in the treatment of salmonella infections but with time there are many resistant organism produced and moreover much safer drugs are available .

3rd generation Cephalosporins quinolones are used

and

If chloramphenicol is used its given 1g 6 hourly for 4 weeks to treat typhoid

Bacterial Meningitis
Excellent activity in meningitis caused by H. Influenza, it is bactericidal and better than ampicillin. 3rd generation cephalosporins are now used due to less toxicity but chloramphenicol remains alternative for treatment of meningitis when Beta Lactams are contraindicated.

Anaerobic-infections
Chloramphenicol is effective against anaerobic bacteria Used for the treatment of serious intraabdominal infections or brain abscesses. (alternative available)

 Rickettsial infections:
Tetracyclines are more preffered agents but chloramphenicol can be used as an alternative treatment in epidemic typhus, murine, scrub and recrudescent typhus as well as Q. fever

 Rocky mountain spotted fever,

 Chills Confusion Fever Headache Muscle pain Rash -- usually starts a few days after the fever; first appears on wrists and ankles as spots that are 1 - 5 mm in diameter, then spreads to most of the body. About one-third of infected people do not get a rash.

Diarrhea Light sensitivity Hallucinations Loss of appetite Nausea Thirst Vomiting

Diagnostic tests
Antibody titer Complete blood count (CBC) Kidney function tests (RFTs) Partial thromboplastin time (PTT) Prothrombin time (PT) Skin biopsy taken from the rash to check for R. rickettsii Urinalysis to check for blood or protein in the urine (urine DR)

Brucellosis
Tetracyclines are more effective when tetracyclines are contraindicated chloramphenicol may be used.

Adverse Effects

 Hematological Toxicity:
The most important adverse effect chloramphenicol is on the bone marrow. of

It causes bone marrow depression, aplastic anemia which may lead to fatal pancytopenia.

 the risk of aplastic anemia does not contraindicate the use of chloramphenicol in situations in which it is necessary.

The drug should never be used, however, in undefined situations or in diseases readily, safely and effectively treatable with other antimicrobial agents.

 Hypersensitivity reactions

Relatively uncommon, macular or vesicular skin rashes occur Fever may appear simultaneously or as a sole manifestation.

Toxic & irritative effects

Nausea, vomiting, unpleasant taste, diarrhea and perineal irritation may follow oral administration.

RARE: blurring of vision, digital paresthesia, optic neuritis in children.

Fatal toxicity in neonates specially premature babies exposed to high dose Grey Baby Syndrome.

Grey baby syndrome

seen in neonates and very young infants receiving high doses of CHLORAMPHENICOL

Toxic blood levels of chloramphenicol occurs due to :

inadeqaute conjugation of chloramphenicol with glucuronic acid because of inadequate activity of glucuronyl transferase in the newborn liver and decreased renal excretion of the chloramphenicol

The infant is cyanosed, is acidotic, has cold peripheries has the signs of all of marked hypotonia, poor feeding, vomiting, loose stools and a distended abdomen

 Similar condition seen in adults as well if the are accidentally exposed to high dose. Death occurs in 40 % cases, those who recover show no sequelae

Drug Interactions
Chloramphenicol inhibits micorsomal cytochrome P450 enzyme thus may prolong the half-lives of drugs metabolized by this enzyme. E.g., Warfarin, dicumarol, phenytoin, chlorpropamide, tolbutamide.

 Phenobarbital chronic use and Rifampin acute administration shorten the half-life of chloramphenicol >>>>>>>> may be due to enzyme induction and may result in sub therapeutic concentrations of the drug.

THERAPEUTICS

TYPHOID FEVER
The patient feels weak, cold and tired. Headache, backache, diarrhea, constipation, loss of appetite Temperature rises and remains high for about 10-14 days. Body temperature typically rises in the evening and drops in the morning.

 Skin eruptions appear, tongue becomes dry and gets white patches in the center, which causes oily taste in mouth and inflamed bones. Fever comes down gradually by the end of fourth week.

Causes of Typhoid Fever

Poor sanitation, contaminated water and infected milk are some of the main factors responsible for typhoid. Flies contaminate the food with germs. People carrying the germs can also spread the disease if they prepare or serve food. Wrong dietary habits and faulty lifestyle lead to accumulation of toxic waste in the body and promotes typhoid fever. Typhoid is common in people who eat more meat and meat products.

 The type of salmonella most commonly associated with infections in humans is called nontyphoidal salmonella >>>>> It is carried by chickens, cows, and reptiles such as turtles, lizards, and iguanas. Another, rarer form of salmonella, typhoidal salmonella (typhoid fever), is carried only by humans and is usually transmitted through direct contact with the fecal matter of an infected person >>>>>> This kind of salmonella infection can lead to high fever, abdominal pain, headache, malaise, lethargy, skin rash, constipation, and delirium. It occurs primarily in developing countries

Commonly used medicines

Ciprofloxacin Oral Cephalosporins mostly parenteral administration Amoxicillin Oral Ampicillin Oral, ampicillin sodium IV

Sulfamethoxazole-trimethoprim Oral Sulfamethoxazole-trimethoprim IV

Chloramphenicol sod succinate IV

Non Pharmacological Management

Complete bed rest is essential. Patient should be kept on a liquid diet of orange, barley juice and milk. Orange juice, especially, hastens recovery as it increases energy, promotes body immunity and increases urinary output.