Chloramphenicol (Systemic)


VA CLASSIFICATION
Primary: AM900

Commonly used brand name(s): Chloromycetin; Novochlorocap.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (systemic)—

Indications

General considerations
Chloramphenicol has in vitro activity against a large number of organisms, including various aerobic gram-positive and gram-negative bacteria, anaerobic bacteria, rickettsiae, spirochetes, and chlamydia. Haemophilus influenzae , Streptococcus pneumoniae , and Neisseria meningitidis are highly susceptible to chloramphenicol, which is considered to be bactericidal against these organisms. Chloramphenicol has bacteriostatic activity against Staphylococcus aureus , Streptococcus pyogenes , S. viridans , group B streptococcus, Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Salmonella typhi , S. paratyphi A , Shigella species, Pseudomonas pseudomallei , and nearly all anaerobes, including Bacteroides fragilis . Bacteria that are generally considered to be resistant to chloramphenicol include Pseudomonas aeruginosa , Acinetobacter species, Enterobacter species, Serratia marcescens , indole positive Proteus species, methicillin-resistant staphylococcus, and Enterococcus faecalis . {32} {46} {51}

Because of this drug's serious toxicities, chloramphenicol is indicated only for the treatment of serious infections in which less toxic antibacterials are ineffective or contraindicated. Other medications, such as the third-generation cephalosporins for the treatment of meningitis, and clindamycin or metronidazole for the treatment of anaerobic infections, have generally replaced chloramphenicol; however, under certain circumstances, chloramphenicol may still be the most appropriate drug to use.

Chloramphenicol is also used in the treatment of rickettsial infections that require parenteral treatment when other antibiotics are contraindicated. {03} {05} {09}

Chloramphenicol should be reserved for serious infections in which less toxic antibacterials are ineffective or contraindicated.

Accepted

Brain abscess (treatment)—Chloramphenicol is indicated in the treatment of brain abscess caused by B. fragilis or other susceptible organisms.

Ehrlichiosis (treatment)—Chloramphenicol is indicated in the treatment of ehrlichiosis caused by Ehrlichia canis .

Meningitis (treatment)—Chloramphenicol is indicated in the treatment of meningitis caused by H. influenzae , S. pneumoniae , and N. meningitidis .

Paratyphoid fever (treatment)—Chloramphenicol is indicated in the treatment of paratyphoid fever caused by S. paratyphi A .

Q fever (treatment)—Chloramphenicol is indicated in the treatment of Q fever caused by Coxiella burnetii .

Rocky Mountain spotted fever (treatment)—Chloramphenicol is indicated in the treatment of Rocky Mountain spotted fever caused by Rickettsia species.

Typhoid fever (treatment)—Chloramphenicol is indicated in the acute treatment of typhoid fever only, caused by S. typhi.

Typhus infections (treatment)—Chloramphenicol is indicated in the treatment of typhus infections caused by Rickettsia species.

—Not all species or strains of a particular organism may be susceptible to chloramphenicol.

Unaccepted
Chloramphenicol is not indicated in the routine treatment of typhoid carrier states; in the treatment of trivial infections, colds, influenza, or throat infections; or in the prophylaxis of infections. {17}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Chloramphenicol: 323.13
    Chloramphenicol palmitate: 561.54
    Chloramphenicol sodium succinate: 445.19

Mechanism of action/Effect:

Chloramphenicol, a broad-spectrum antibiotic, is bacteriostatic. However, it may be bactericidal in high concentrations or when used against highly susceptible organisms. {22}

Chloramphenicol, which is lipid soluble, diffuses through the bacterial cell membrane and reversibly binds to the 50 S subunit of bacterial ribosomes where transfer of amino acids to growing peptide chains is prevented (perhaps by suppression of peptidyl transferase activity), thus inhibiting peptide bond formation and subsequent protein synthesis. {21}

The mechanism for the irreversible aplastic anemia following use of chloramphenicol has not been established.

The mechanism for the dose-related reversible bone-marrow depression during and following use of chloramphenicol is thought to be by inhibition of mitochondrial protein synthesis in bone-marrow cells. {22}

Absorption:

Rapidly and completely absorbed from gastrointestinal tract. {17}

Well absorbed after intramuscular administration; achieves serum concentrations comparable to intravenous administration. {42}

Intravenous bioavailability—70%. {22}

Oral bioavailability—80%. {22}

Distribution:


Chloramphenicol diffuses rapidly and is widely, but not uniformly, distributed throughout the body to {17}:

Liver and kidneys: Highest concentrations.

Urine: High concentrations.

Placenta: Fetal serum concentrations may be 30 to 80% of maternal serum concentrations.

Eye: Therapeutic concentrations in aqueous and vitreous humor.

Cerebrospinal fluid (CSF): Concentrations may be 21 to 50% of serum concentrations through uninflamed meninges and may be 45 to 89% of serum concentrations through inflamed meninges.

Other: Pleural fluid, ascitic fluid, synovial fluid, breast milk, and saliva (bitter aftertaste).

Vol D = 0.6–1.0 L/kg. {22}


Protein binding:

Adults—Moderate (50–60%). {21} {22}

Premature neonates—Low (32%). {21} {22}

Biotransformation:

Hepatic (free drug); 90% conjugated to inactive glucuronide. {22}

Chloramphenicol palmitate is hydrolyzed to free drug in the gastrointestinal tract prior to absorption. {22}

Chloramphenicol sodium succinate is hydrolyzed to free drug in the plasma, liver, lungs, and kidneys. {22}

In the fetus and neonates, the immature liver cannot conjugate chloramphenicol, and toxic concentrations of active drug accumulate. In neonates and infants this may result in the ``gray syndrome.'' {22}

Half-life:


Adults {22} {39}:

Normal renal and hepatic function: 1.5 to 3.5 hours.

Impaired renal function: 3 to 4 hours.

Severely impaired hepatic function: Prolonged (4.6 to 11.6 hours).



Children (1 month to 16 years old):

3 to 6.5 hours. {41} {42} {43} {44}



Infants {22}:

1 to 2 days old: 24 hours or longer; highly variable, especially in low-birth-weight infants.

10 to 16 days old: 10 hours.


Time to peak serum concentration:

Intravenous—1 to 1.5 hours. {32} {33}

Oral—1 to 3 hours. {22}

Peak serum concentration:

Adults—Oral, 12.5 mg per kg of body weight (mg/kg): 11.2 to 18.4 mcg/mL. {17}

Children—Oral and intravenous: 25 mg/kg—19 to 28 mcg/mL. {32} {42} {45}

Elimination:
    Renal, by glomerular filtration; 5 to 10% excreted unchanged within 24 hours; 80% rapidly excreted by tubular secretion as inactive metabolites. Inactive metabolites can accumulate in premature and newborn infants because of immaturity of renal tubular secretion mechanisms. {22}
    Fecal/biliary; small amounts excreted unchanged following oral administration. {22}
    Dialysis—Dialysis does not remove significant amounts of chloramphenicol from the blood. {21} Charcoal hemoperfusion has been reported to lower blood concentrations in an infant. {31}


Precautions to Consider

Pregnancy/Reproduction

Chloramphenicol readily crosses the placenta; fetal serum concentrations may be 30 to 80% of maternal serum concentrations. Although birth defects in humans have not been documented, use is not recommended in pregnancy at term or during labor because of potential toxicity (``gray syndrome'' or bone marrow depression) in premature or full-term infants. {23}

Breast-feeding

Chloramphenicol is excreted in breast milk in concentrations up to 25 mcg per mL. Use is not recommended in nursing mothers because of the possibility of adverse effects, especially bone marrow depression, in the infant. {23}

Pediatrics

In the fetus and neonates, the immature liver cannot conjugate chloramphenicol, and toxic concentrations of active drug accumulate. In neonates and infants this may result in the ``gray syndrome.'' {21}

In infants 1 to 2 days old, the half-life is 24 hours or longer and may be highly variable, especially in low-birth-weight infants. In infants 10 to 16 days old, the half-life is 10 hours. {22}

Inactive metabolites can accumulate in premature and newborn infants because of immaturity of renal tubular secretion mechanisms. {21}

Serum concentrations must be performed in pediatric patients with impaired or immature metabolic functions or in patients who are receiving medications that are also metabolized by the liver (e.g., phenytoin, phenobarbital, acetaminophen, theophylline).


Geriatrics


No information is available on the relationship of age to the effects of chloramphenicol in geriatric patients.


Dental

The bone marrow–depressant effects of chloramphenicol may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alfentanil    (chronic preoperative or perioperative use of chloramphenicol, an hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil {05})


» Anticonvulsants, hydantoin or{24}
Blood dyscrasia–causing medications (See Appendix II ) or
» Bone marrow depressants, other (See Appendix II ) or{17}
» Radiation therapy    (concurrent use with chloramphenicol may increase the bone marrow–depressant effects of these medications and radiation therapy; dosage reduction may be required)


» Antidiabetic agents, oral    (concurrent use of chloramphenicol with tolbutamide and chlorpropamide may enhance their hypoglycemic effect by inhibiting the hepatic metabolism of these medications and increasing their serum levels; dosage adjustments may be necessary {27}; glipizide and glyburide, due to their non-ionic binding characteristics, may not be affected as much as the other oral antidiabetic agents; however, caution with concurrent use is recommended {29})


Contraceptives, estrogen-containing, oral    (concurrent long-term use of chloramphenicol may result in reduced contraceptive reliability and increased incidence of breakthrough bleeding {28})


» Clindamycin or
» Erythromycins or
» Lincomycin    (may be displaced from or prevented from binding to 50 S subunits of bacterial ribosomes by chloramphenicol, thus antagonizing the effects of erythromycins and lincomycins; concurrent use is not recommended {30})


Hepatic enzyme inducers    (concurrent use of chloramphenicol with hepatic microsomal enzyme inducing drugs, including phenobarbital and rifampin, can increase the metabolism of chloramphenicol, decreasing chloramphenicol serum concentrations {34} {35} {36})


Penicillins    (since bacteriostatic drugs may interfere with the bactericidal effects of penicillins in the treatment of meningitis or in other situations in which a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy; however, chloramphenicol and ampicillin are sometimes administered concurrently in pediatric patients {25})


» Phenobarbital or
» Phenytoin or
» Warfarin or
» Other medications metabolized by mixed-function oxidase system    (inhibition of the cytochrome P-450 enzyme system by chloramphenicol may cause a decrease in the hepatic metabolism of these medications, resulting in delayed elimination and increased blood concentrations {24} {37} {38})


Vitamin B 1 2    (concurrent use may antagonize hematopoietic response to vitamin B 1 2; monitoring of hematologic status or use of an alternate antibiotic is recommended {26})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bentiromide    (concurrent administration of chloramphenicol during a bentiromide test period will invalidate test results since chloramphenicol is also metabolized to arylamines and will thus increase the percent of PABA recovered; discontinuation of chloramphenicol at least 3 days prior to the administration of bentiromide is recommended)


Urine glucose determinations    (chloramphenicol may give false-positive test results with copper sulfate urine glucose tests)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Previous allergy or toxic reaction to chloramphenicol{17}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression    (chloramphenicol may cause a dose-related bone marrow depression, an idiosyncratic aplastic anemia, and other blood dyscrasias)


» Hepatic function impairment    (chloramphenicol is metabolized in the liver; patients with impaired or immature hepatic or renal function, especially neonates and infants, or adults with both impaired hepatic and renal function, may require a reduction in dose; serum concentrations should be monitored {17})


» Risk-benefit should be considered in patients who have had previous cytotoxic drug therapy or radiation therapy also.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Chloramphenicol levels, serum    (serum concentrations must be performed in low-birth-weight infants because the pharmacokinetics of chloramphenicol are so variable in this age group; serum concentrations should also be monitored in patients with impaired or immature metabolic functions or in patients who are receiving medications that are also metabolized by the liver; the desired serum concentration should fall within the range of 10 to 25 mcg/mL, the concentration to which most susceptible organisms respond; concentrations in excess of these increase the risk of reversible bone marrow depression and ``gray syndrome'' {04})


» Complete blood counts (CBCs)    (may be required frequently during therapy to detect dose-related reversible bone marrow depression; chloramphenicol should be discontinued if reticulocytopenia, leukopenia, thrombocytopenia, anemia, or other blood dyscrasias occur; {06} {07} {08} however, CBCs are not useful in predicting aplastic anemia, which usually appears after treatment has been completed)

    (patients should be informed of the importance of having blood counts followed closely during therapy)




Side/Adverse Effects

Note: The hematologic toxicity of chloramphenicol can manifest itself in 1 of 2 ways—either as a reversible bone marrow depression or an idiosyncratic aplastic anemia. Bone marrow depression is dose-related and most commonly seen when serum concentrations exceed 25 mcg/mL. Bone marrow changes are usually reversible when chloramphenicol is discontinued. Aplastic anemia is an idiosyncratic reaction that occurs in 1 of every 25,000 to 40,000 courses of treatment. It is not related to dose or duration of therapy. Most cases have been associated with oral chloramphenicol, and the onset of aplasia may not occur until weeks or months after treatment with chloramphenicol has been discontinued. {45} {46}
Gray syndrome (or ``gray baby syndrome'') almost always occurs in newborn infants treated with inappropriately high doses of chloramphenicol. Typically, the infant has been started on chloramphenicol within the first 48 hours of life; symptoms first appear after 3 to 4 days of continued treatment with high doses of chloramphenicol; and serum levels are high, often between 40 and 200 mcg/mL. If caught early and chloramphenicol is discontinued, the infant may have a complete recovery. On rare occasion, older patients, including adults with severe liver disease, have also had a gray syndrome–type reaction. {47} {48}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Blood dyscrasias (pale skin; sore throat and fever; unusual bleeding or bruising; unusual tiredness or weakness)

Incidence rare
    
Gray syndrome (abdominal distension; blue-gray skin color; low body temperature; uneven breathing; unresponsiveness; cardiovascular collapse)—in neonates only
    
hypersensitivity reactions (skin rash; fever; shortness of breath)
    
neurotoxic reactions (confusion; delirium; headache)
    
optic neuritis (eye pain, blurred vision, or loss of vision)
    
peripheral neuritis (numbness, tingling, burning pain, or weakness in the hands or feet)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Gastrointestinal reaction (diarrhea; nausea; vomiting)



Those indicating possible fatal, irreversible bone marrow depression, leading to aplastic anemia, and the need for immediate medical attention if they occur weeks or months after medication is discontinued
    
Pale skin
    
sore throat and fever
    
unusual bleeding or bruising
    
unusual tiredness or weakness




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Chloramphenicol (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergies or toxic reactions to chloramphenicol

Pregnancy—Chloramphenicol crosses the placenta; use at term or during labor may cause ``gray syndrome'' in infants





Breast-feeding—Chloramphenicol is excreted in breast milk; may cause bone marrow depression in the infant





Use in children—Because of possible accumulation and toxic reactions, serum concentrations must be measured in premature and newborn infants






Dental—May result in an increased incidence of infection, delayed healing, and gingival bleeding
Other medications, especially alfentanil, hydantoin anticonvulsants, bone marrow depressants, radiation therapy, oral antidiabetic agents, erythromycins, lincomycins, phenobarbital, phenytoin, warfarin, or other medicines metabolized by mixed-function oxidase system
Other medical problems, especially bone marrow depression, liver dysfunction, previous cytotoxic drug therapy, or radiation therapy

Proper use of this medication
Taking on an empty stomach

Proper administration technique for oral liquids

» Compliance with full course of therapy

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within a few days

» Regular visits to physician to check for blood problems

Using caution in use of regular toothbrushes, dental floss, and toothpicks; completing dental work prior to initiation of therapy or deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene

» Diabetics: False-positive reactions with copper sulfate urine glucose tests may occur


Side/adverse effects
May also cause bone marrow aplasia and ``gray syndrome''

Signs of potential side effects, especially blood dyscrasias, gray syndrome, optic neuritis, peripheral neuritis, neurotoxic reactions, or hypersensitivity reactions


General Dosing Information
Treatment should be continued no longer than required to produce a cure, yet long enough to provide little or no risk of relapse.

Repeated courses of the drug should be avoided if at all possible since reversible bone marrow depression may occur.

The serum chloramphenicol concentration should fall within the range of 10 to 25 mcg/mL, the concentration to which most susceptible organisms respond; concentrations higher than 30 mcg/mL increase the risk of bone marrow depression and ``gray syndrome.'' {49}

For oral dosage forms only
Chloramphenicol should preferably be taken with a full glass (240 mL) of water on an empty stomach (either 1 hour before or 2 hours after meals) to optimize absorption.

Chloramphenicol palmitate must be hydrolyzed in the gastrointestinal tract to chloramphenicol before being absorbed. The rate of absorption may be decreased in neonates or increased in older children, depending on the individual rate of hydrolysis. Serum concentrations are usually similar to those resulting from oral base administration of chloramphenicol.


Oral Dosage Forms

CHLORAMPHENICOL CAPSULES USP

Usual adult and adolescent dose
Antibacterial
Oral, 12.5 mg (base) per kg of body weight every six hours. {17}


Usual adult prescribing limits
Up to a maximum of 4 grams (base) daily.

Usual pediatric dose
Antibacterial {17}
Premature and full-term infants up to 2 weeks of age: Oral, 6.25 mg (base) per kg of body weight every six hours.

Infants 2 weeks of age and over: Oral, 12.5 mg (base) per kg of body weight every six hours; or 25 mg per kg of body weight every twelve hours.


Note: In severe infections, such as bacteremia or meningitis, doses up to 75 to 100 mg (base) per kg of body weight daily may be used. {17}
Serum determinations are recommended in patients with impaired or immature metabolic functions.


Strength(s) usually available
U.S.—


250 mg (base) (Rx) [Chloromycetin][Generic]

Canada—


250 mg (base) (Rx) [Novochlorocap]

Packaging and storage:
Store below 30 °C (86 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Continue medicine for full time of treatment.
   • Take on empty stomach.


CHLORAMPHENICOL PALMITATE ORAL SUSPENSION USP

Usual adult and adolescent dose
See Chloramphenicol Capsules USP .

Usual adult prescribing limits
See Chloramphenicol Capsules USP .

Usual pediatric dose
See Chloramphenicol Capsules USP .

Strength(s) usually available
U.S.—


150 mg (base) per 5 mL (Rx) [Chloromycetin (sodium benzoate 2.5 mg per 5 mL)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Auxiliary labeling:
   • Shake well.
   • Continue medicine for full time of treatment.
   • Take on empty stomach.

Note: When dispensing, include a calibrated liquid-measuring device.


Additional information:
The oral suspension is tasteless.



Parenteral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of chloramphenicol base.


STERILE CHLORAMPHENICOL SODIUM SUCCINATE USP

Usual adult and adolescent dose
Antibacterial
Intravenous, 12.5 mg (base) per kg of body weight every six hours. {17}


Usual adult prescribing limits
Up to a maximum of 4 grams (base) daily.

Usual pediatric dose
Antibacterial
Premature and full-term infants up to 2 weeks of age: Intravenous, 6.25 mg (base) per kg of body weight every six hours.

Infants 2 weeks of age and over: Intravenous, 12.5 mg (base) per kg of body weight every six hours; or 25 mg per kg of body weight every twelve hours.


Note: In severe infections, such as bacteremia or meningitis, doses up to 75 to 100 mg (base) per kg of body weight daily may be used. {17}
Serum determinations are recommended in patients with impaired or immature metabolic functions.


Size(s) usually available:
U.S.—


1 gram (base) (Rx) [Chloromycetin (sodium 2.25 mEq per gram)][Generic]

Canada—


1 gram (base) (Rx) [Chloromycetin]

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
To prepare a 10% (100-mg-per-mL) solution, add 10 mL of an aqueous diluent such as sterile water for injection or 5% dextrose injection to each 1-gram vial.

Stability:
After reconstitution, solutions (100-mg-per-mL) retain their potency for 2 to 30 days if stored at room temperature or if refrigerated, depending on the manufacturer.

Diluted solutions are stable for 24 to 48 hours if stored at room temperature or if refrigerated, depending on the manufacturer.

If frozen, solutions retain their potency for up to 6 months, depending on the manufacturer.

Do not use if solution is cloudy.

Additional information:
Chloramphenicol sodium succinate must be hydrolyzed in the body to chloramphenicol; therefore, there may be a delay in achieving adequate serum concentrations of active drug.

May be given intravenously over at least a 1-minute period.

Chloramphenicol may also be given intramuscularly, achieving serum concentrations comparable to intravenous administration. {42}



Revised: 06/20/1995



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