CHLORAMPHENICOL SOD SUCCINATE

General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Powder Vials for Injection
Reconstitution
-Reconstitute 1 g with 10 mL of an aqueous diluent (i.e., Sterile Water for Injection or 5% Dextrose Injection) to yield 100 mg/mL.

Intermittent IV Push
-Inject IV over at least 1 minute.

The gray-baby syndrome is an adverse reaction usually seen in premature or newborn infants receiving chloramphenicol. It is characterized by abdominal distension, with or without emesis; progressive pallid cyanosis; and vasomotor collapse, possibly accompanied by irregular breathing. The syndrome can result in death within a few hours of symptom onset. It is believed to be due to the variable maturity of the metabolic functions of the liver and kidney in premature infants and neonates less than 2 weeks of age, which results in high drug concentrations. In most reported cases, symptoms first appeared after 3 to 4 days of treatment with high doses (i.e., with serum concentrations > 90 mcg/ml). Most cases result from institution of therapy within the first 48 hours of life, although one case has been reported in a newborn infant born to a mother receiving chloramphenicol during labor. Discontinue use of the drug at the first sign of this syndrome; termination of therapy may reverse the process and lead to recovery.

Aplastic anemia, hypoplastic anemia, thrombocytopenia, pancytopenia, and neutropenia have all occurred following short-term and long-term therapy as a result of bone marrow suppression. Bone marrow toxicity may be dose-related. Non-dose-related, irreversible bone marrow suppression can result in aplastic anemia and has a high mortality rate. This type of aplasia or hypoplasia can develop months after the drug has been discontinued, or from a single dose. Reversible bone marrow suppression usually is dose-related and is characterized by anemia, reticulocytopenia, leukopenia, or thrombocytopenia. It is believed that bone marrow toxicity is more common when peak serum concentrations exceed 25 mcg/ml. There have also been reports of aplastic anemia attributed to chloramphenicol which later terminated in leukemia. Patients should be monitored for a declining hematocrit and a rising serum iron if chloramphenicol serum concentrations are not available. Paroxysmal nocturnal hemoglobinuria has also been reported.

Optic neuritis, which can cause blindness, or peripheral neuritis can result from long-term therapy and requires immediate discontinuation of chloramphenicol. Other adverse neurotoxic effects include headache, mild depression, confusion, and delirium. Patients should be monitored for other signs of peripheral neuropathy.

GI effects may occur in low incidence during therapy with chloramphenicol and can include nausea, vomiting, diarrhea, glossitis, stomatitis, and enterocolitis. Adverse GI symptoms should be reported immediately because they can indicate more severe reactions.

Maculopapular rash, vesicular rash, fever, angioedema, anaphylactoid reactions, and urticaria can occur from administration of chloramphenicol. Herxheimer-like reactions have been reported during therapy for typhoid fever, syphilis, and brucellosis.

Interstitial nephritis, a hypersensitivity reaction, although uncommon, has been reported with chloramphenicol therapy.

Chloramphenicol has been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly, is associated with fever above 38 degrees C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. Drugs are the main cause of AGEP. A period of 2-3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, pruritus, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome.

Chloramphenicol may reduce absorption of vitamin B12 leading to vitamin B12 deficiency. Supplementation of vitamin B12 should be considered during extended therapy.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with chloramphenicol. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.

Systemic chloramphenicol is contraindicated for minor infections, colds and influenza, and as prophylaxis because of the potential for toxicity. Therapeutic benefits generally do not outweigh the risks. Administration should occur in a setting where appropriate serum concentration and patient monitoring can be undertaken. Serum concentrations and patient response are unpredictable. All patients receiving systemic chloramphenicol should have blood concentrations monitored.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, such as chloramphenicol, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Chloramphenicol should be used with caution in patients with bone marrow suppression. Chloramphenicol is associated with serious and fatal blood dyscrasias such as aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia. Bone marrow suppression appears to be dose-related and has occurred after both short- and long-term therapy. Chloramphenicol is also associated with aplastic anemia which later terminated in leukemia. Do not use chloramphenicol when less potentially dangerous agents will be effective. The drug must not be used for trivial infections or where it is not indicated, as in colds, influenza, throat infections; or in the prophylaxis of bacterial infections. Adequate blood studies must be performed at baseline and every 2 days during therapy. Although blood studies may detect early peripheral blood changes (i.e., leukopenia, reticulocytopenia, or granulocytopenia) before they become irreversible, they can not be reliable in detecting bone marrow depression prior to development of aplastic anemia. It is desirable to hospitalize the patient to aid in monitoring during therapy. Prolonged or repeated use of topical chloramphenicol should be avoided because it could be absorbed systemically, resulting in marrow hypoplasia, aplastic anemia, and, possibly, death.

Use extreme caution when considering treatment with chloramphenicol in infants. Premature infants and neonates less than 2 weeks of age, in particular, have variable maturity of the metabolic functions of the liver and kidney. With immature liver and kidney function, high drug concentrations are found which tend to increase with succeeding doses. This can result in the 'gray-baby' syndrome which is characterized by abdominal distension, with or without vomiting; progressive pallid cyanosis; and vasomotor collapse, possibly accompanied by irregular breathing. The syndrome can result in death within a few hours of symptom onset. In most reported cases, symptoms first appeared after 3 to 4 days of treatment with high doses (i.e., with serum concentrations > 90 mcg/ml). Most cases result from institution of therapy within the first 48 hours of life, although one case has been reported in a newborn infant born to a mother receiving chloramphenicol during labor. Discontinue use of the drug at the first sign of this syndrome; termination of therapy may reverse the process and lead to recovery.

Administer chloramphenicol with caution to patients with hepatic disease, renal impairment, or in those with glucose 6-phosphate dehydrogenase deficiency (G6PD deficiency). Children with impaired liver or kidney function may retain excessive amounts of the drug. If administered, the dosage should be adjusted accordingly, preferably using blood concentrations as a guide. Use of the drug in patients with Mediterranean form of G6PD deficiency has resulted in cases of hemolytic anemia; this adverse reaction does not appear to occur in patients with type A G6PD deficiency.

Chloramphenicol can induce acute attacks of porphyria in patients with a history of acute intermittent porphyria; avoid use of the drug in these patients.

Description: Chloramphenicol is a broad spectrum, synthetic antibiotic. Despite the broad spectrum of activity, chloramphenicol has limited clinical use due to severe and potentially fatal adverse reactions, most notably the gray-baby syndrome. The gray-baby syndrome has been seen after administration to neonates and infants and is thought to be due to the patients' inability to hepatically conjugate or excrete the drug; death could result within a few hours of symptom onset. Additionally, severe and sometimes fatal blood dyscrasias limit use of the drug to serious infections for which other antibiotics are ineffective or contraindicated; blood studies are required at baseline and approximately every two days during therapy. Despite the potential for serious toxicity, chloramphenicol is FDA-approved for use in pediatric patients as young as neonates.

NOTE: Due to the risk of potentially fatal toxicity, chloramphenicol must only be used to treat serious infections for which other antibiotics are ineffective or contraindicated.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Chlamydia sp., Chlamydophila psittaci, Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Rickettsia rickettsii, Rickettsia sp., Salmonella enterica serotype Typhi , Salmonella sp.
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Francisella tularensis, Yersinia pestis
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of serious infections for which less potentially dangerous drugs are ineffective or contraindicated, including various serious gram-negative bacterial infections causing bacteremia, Haemophilus influenzae infections, cystic fibrosis, and lymphogranuloma psittacosis group infections:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 24 hours is supported by limited data in neonates and guidelines. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Neonates 8 days and older: 25 mg/kg/dose IV every 12 to 24 hours is supported by limited data in neonates and guidelines. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger and up to 50 mg/kg/day IV divided every 6 hours in neonates older than 14 days; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Infants, Children, and Adolescents: 50 mg/kg/day IV divided every 6 hours. For infections caused by moderately resistant organisms, doses up to 100 mg/kg/day may be required. Reduce dosage to 50 mg/kg/day as soon as possible. Adjust dose based on serum concentrations.

For the treatment of salmonella infections, including salmonellosis and typhoid fever:
-for the treatment of salmonellosis:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 24 hours is supported by limited data in neonates and guidelines. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Neonates 8 days and older: 25 mg/kg/dose IV every 12 to 24 hours is supported by limited data in neonates and guidelines. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger and up to 50 mg/kg/day IV divided every 6 hours in neonates older than 14 days; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Infants, Children, and Adolescents: 50 to 100 mg/kg/day IV divided every 6 hours. Reduce dosage to 50 mg/kg/day IV as soon as possible. Adjust dose based on serum concentrations.
-for the treatment of fully sensitive severe typhoid fever:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 24 hours for 14 to 21 days as an alternative is supported by limited data in neonates and guidelines. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Neonates 8 days and older: 25 mg/kg/dose IV every 12 to 24 hours for 14 to 21 days as an alternative is supported by limited data in neonates and guidelines. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger and up to 50 mg/kg/day IV divided every 6 hours in neonates older than 14 days; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Infants, Children, and Adolescents: 100 mg/kg/day IV divided every 6 hours for 14 to 21 days as an alternative. Reduce dosage to 50 mg/kg/day as soon as possible. Adjust dosage based on serum concentrations.

For the treatment of plague* infection:
-for the treatment of bubonic or pharyngeal plague*:
Intravenous dosage:
Neonates 0 to 14 days: 6.25 mg/kg/dose IV every 6 hours for 10 to 14 days as an alternative therapy. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients infected after intentional release of Y. pestis.
Neonates 15 days and older: 12.5 mg/kg/dose IV every 6 hours for 10 to 14 days as an alternative therapy. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients infected after intentional release of Y. pestis.
Infants, Children, and Adolescents: 12.5 to 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for 10 to 14 days as an alternative therapy. Monotherapy is recommended for stable patients with naturally occurring plague, although dual therapy can be considered for patients with large buboes. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients infected after intentional release of Y. pestis.
-for the treatment of pneumonic or septicemic plague*:
Intravenous dosage:
Neonates 0 to 14 days: 6.25 mg/kg/dose IV every 6 hours for 10 to 14 days as an alternative therapy. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients with severe disease and patients infected after intentional release of Y. pestis.
Neonates 15 days and older: 12.5 mg/kg/dose IV every 6 hours for 10 to 14 days as an alternative therapy. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients with severe disease and patients infected after intentional release of Y. pestis.
Infants, Children, and Adolescents: 12.5 to 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for 10 to 14 days as an alternative therapy. Monotherapy can be considered for mild-to-moderate disease in patients with naturally occurring plague. Use dual therapy with 2 distinct classes of antimicrobials for initial treatment in patients with severe disease and patients infected after intentional release of Y. pestis.
-for the treatment of plague meningitis*:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 24 hours in combination with levofloxacin for 10 to 14 days. For patients with secondary plague meningitis, chloramphenicol should be added to the existing antimicrobial regimen and the entire regimen should be continued for an additional 10 days.
Neonates 8 days and older: 25 mg/kg/dose IV every 12 hours in combination with levofloxacin for 10 to 14 days. For patients with secondary plague meningitis, chloramphenicol should be added to the existing antimicrobial regimen and the entire regimen should be continued for an additional 10 days.
Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours in combination with levofloxacin or moxifloxacin for 10 to 14 days. For patients with secondary plague meningitis, chloramphenicol should be added to the existing antimicrobial regimen and the entire regimen should be continued for an additional 10 days.

For the initial treatment of tularemia* infection due to exposure to Francisella tularensis in individual patients or in a contained casualty setting:
Intravenous dosage:
Children and Adolescents: 15 mg/kg/dose IV every 6 hours for 14-21 days. Streptomycin and gentamicin are considered the drugs of choice; chloramphenicol, along with doxycyline and ciprofloxacin, are alternative agents. Switch to oral antibiotic therapy when clinically indicated.

For the treatment of anthrax*:
-for the treatment of systemic anthrax* without aerosol exposure, including those with signs and symptoms of meningitis, as part of combination therapy:
Intravenous dosage:
Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for at least 14 days; may consider step-down to oral therapy.
-for the treatment of systemic anthrax* with aerosol exposure, including those with signs and symptoms of meningitis, as part of combination therapy:
Intravenous dosage:
Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for at least 14 days; may consider step-down to oral therapy.
Immunocompromised Infants, Children, and Adolescents: 25 mg/kg/dose (Max: 1 g/dose) IV every 6 hours for at least 14 days; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course from illness onset.

For the treatment of serious Rickettsial infections, including Rocky Mountain spotted fever:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 24 hours as an alternative is supported by limited data in neonates and guidelines. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Neonates 8 days and older: 25 mg/kg/dose IV every 12 to 24 hours as an alternative is supported by limited data in neonates and guidelines. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger and up to 50 mg/kg/day IV divided every 6 hours in neonates older than 14 days; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Infants, Children, and Adolescents: 50 to 100 mg/kg/day IV divided every 6 hours as an alternative. Reduce dosage to 50 mg/kg/day IV as soon as possible. Adjust dose based on serum concentrations.

For the treatment of bartonellosis*, including Oroya fever*:
Intravenous dosage:
Infants, Children, and Adolescents: 50 to 75 mg/kg/day IV divided every 6 hours for 14 days plus a beta-lactam as first-line therapy.

For the treatment of meningitis:
-for the treatment of meningococcal meningitis as well as meningitis due to H. influenzae:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 24 hours for 7 days. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Neonates 8 days and older: 50 mg/kg/day IV divided every 12 to 24 hours for 7 days. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger and up to 50 mg/kg/day IV divided every 6 hours in neonates older than 14 days; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Infants, Children, and Adolescents: 50 to 100 mg/kg/day (Max: 4 g/day) IV divided every 6 hours for 7 days. Reduce dosage to 50 mg/kg/day as soon as possible. Adjust dose based on serum concentrations.
-for the treatment of pneumococcal meningitis:
Intravenous dosage:
Neonates 0 to 7 days: 25 mg/kg/dose IV every 24 hours for 10 to 14 days. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Neonates 8 days and older: 50 mg/kg/day IV divided every 12 to 24 hours for 10 to 14 days. The FDA-approved dosage is 25 mg/kg/day IV divided every 6 hours in neonates 14 days and younger and up to 50 mg/kg/day IV divided every 6 hours in neonates older than 14 days; however, dosing modifications for premature neonates are not specified and the frequency specified in the product labeling is higher than what is supported in pharmacokinetic studies in neonates. Adjust dose based on serum concentrations.
Infants, Children, and Adolescents: 50 to 100 mg/kg/day (Max: 6 g/day) IV divided every 6 hours for 10 to 14 days. Reduce dosage to 50 mg/kg/day as soon as possible. Adjust dose based on serum concentrations.

Therapeutic Drug Monitoring:
Serum concentrations must be monitored in neonates because the pharmacokinetics of chloramphenicol are highly variable in this age group. Blood concentrations should be monitored at appropriate intervals in patients with renal or hepatic impairment and in infants due to their immature metabolic processes. For infections other than meningitis, peak concentrations should be in the range 10-20 mcg/ml and trough concentrations 5-10 mcg/ml. For meningitis, peak concentrations of 15-25 mcg/ml and trough concentrations of 5-15 mcg/ml may be desired. Peak serum concentrations should be checked 1.5 hours after completion of IV dosing. Trough levels should be drawn 1 hour prior to the next dose and may be preferable. Additionally, blood studies are required at baseline and every two days during chloramphenicol therapy to detect dose-related reversible bone marrow depression. Discontinue therapy if reticulocytopenia, leukopenia, thrombocytopenia, anemia, or other blood dyscrasias are detected. However, such studies do not exclude the possibility of post-treatment irreversible bone marrow depression.

Maximum Dosage Limits:
-Neonates
0 to 7 days: 25 mg/kg/day IV.
8 to 14 days: 25 mg/kg/day IV is FDA-approved; however, doses up to 50 mg/kg/day IV have been used off-label.
15 days and older: 50 mg/kg/day IV.
-Infants
100 mg/kg/day IV.
-Children
100 mg/kg/day IV.
-Adolescents
100 mg/kg/day IV.

Patients with Hepatic Impairment Dosing
Chloramphenicol is metabolized by the liver. Patients with hepatic impairment or immature hepatic function may require a dosage reduction. Specific dosage adjustment guidelines are not available; serum concentrations should be monitored.

Patients with Renal Impairment Dosing
No quantitative recommendations are available; however, dosage should be modified based on clinical response, degree of renal impairment, and serum chloramphenicol concentrations.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Chloramphenicol is usually bacteriostatic but may be bactericidal in high concentrations or against more susceptible organisms such as H. influenzae, N. meningitidis, and S. pneumoniae. Antibiotic activity appears to result from inhibition of protein synthesis of bacterial cells. Chloramphenicol reversibly binds to the 50 S subunit of bacterial ribosomes, which inhibits peptide bond formation. Chloramphenicol also inhibits mitochondrial protein synthesis in both bacterial and mammalian cells via its effects on the 70 S ribosome. The protein synthesis of rapidly proliferating cells may be affected, especially mammalian erythrocytes, explaining the mechanism of reversible bone marrow suppression.

The susceptibility interpretive criteria for chloramphenicol are delineated by pathogen. The MICs are defined for anaerobes, Staphylococcus sp., Enterococcus sp., Enterobacterales, B. cepacia, S. maltophilia, Vibrio sp., other non-Enterobacterales, Y. pestis, Leuconostoc sp., Pediococcus sp., Bacillus sp. (excluding B. anthracis), and Aeromonas sp. as susceptible at 8 mcg/mL or less, intermediate at 16 mcg/mL, and resistant at 32 mcg/mL or more. The MICs are defined for Pasteurella sp. as susceptible at 2 mcg/mL or less. The MICs are defined for F. tularensis as susceptible at 8 mcg/mL or less. The MICs are defined for S. pneumoniae, Abiotrophia sp., and Granulicatella sp. as susceptible at 4 mcg/mL or less and resistant at 8 mcg/mL or more. The MICs are defined for H. influenzae, H. parainfluenzae, N. meningitidis, and M. catarrhalis as susceptible at 2 mcg/mL or less, intermediate at 4 mcg/mL, and resistant at 8 mcg/mL or more. The MICs are defined for beta-hemolytic Streptococcus sp., Streptococcus sp. Viridans group, Aggregatibacter sp., Cardiobacterium sp., E. corrodens, and Kingella sp. as susceptible at 4 mcg/mL or less, intermediate at 8 mcg/mL, and resistant at 16 mcg/mL or more.

Pharmacokinetics: Chloramphenicol is administered intravenously; the oral, ophthalmic, and topical formulations are no longer marketed within the United States.

Due to its low molecular weight, lipid solubility, and relatively low protein binding (25-50%), chloramphenicol is widely distributed into most body tissues and fluids with an apparent volume of distribution of 100 L. Drug distribution is rapid and non-uniform, with highest concentrations found in the liver and kidneys and lowest in the brain and cerebrospinal fluid (CSF). However, compared with other antibiotics, CSF concentrations are still significant, even without inflamed meninges, at 30-50% of serum concentrations. Measurable concentrations have also been detected in aqueous and vitreous humor, as well as ascitic, pleural, and synovial fluids. Metabolism occurs in the liver, where approximately 90% of the parent drug is conjugated to an inactive metabolite. The remaining 8-12% is excreted unchanged in the urine, with small amounts found in bile and feces. In adults with normal renal and hepatic function, the plasma half-life is 4.1 hours.

Affected cytochrome P450 isoenzymes: CYP2C19, CYP3A4, and CYP2D6
Chloramphenicol is a potent inhibitor of the hepatic microsomal cytochrome P450 enzymes CYP2C19 and CYP3A4 in human liver microsomes. Chloramphenicol also weakly inhibits CYP2D6.


-Route-Specific Pharmacokinetics
Oral Route
Free chloramphenicol is rapidly absorbed from the gastrointestinal (GI) tract, with peak serum concentrations (Cmax) occurring within 1 hour of an adult dose. Peak concentrations rise with repeated administration. Chloramphenicol palmitate is a prodrug that requires hydrolysis in the upper GI tract to become active chloramphenicol. Due to varying hydrolysis rates, serum concentrations of the active drug may differ after administration of chloramphenicol palmitate.

Intravenous Route
The intravenous formulation, chloramphenicol sodium succinate, is a water-soluble ester prodrug that is rapidly hydrolyzed in the body to become active chloramphenicol. Due to incomplete hydrolysis, the intravenous formulation produces chloramphenicol serum concentration 30% lower than those obtained after oral administration.

Intramuscular Route
Chloramphenicol is ineffective when administered via the intramuscular route. Lower serum concentrations associated with the intramuscular route is theorized to be due to delayed absorption from the injection site.


-Special Populations
Pediatrics
Premature Neonates and Neonates <= 14 days
Premature and newborn infants have immature metabolic functions which may result in high and escalating chloramphenicol serum concentrations. Dose reductions and serum drug monitoring are required.

Neonates > 14 days, Infants, and Children
The pediatric population may experience variations in the maturity of metabolic function of the liver and kidney, resulting in high or escalating chloramphenicol serum concentrations. Carefully monitor serum drug concentrations and reduce dose if necessary.

Hepatic Impairment
The metabolism (conjugation) of chloramphenicol may be impaired in patients with hepatic dysfunction, resulting in elevated serum concentrations of active chloramphenicol. Monitor serum drug concentration closely.

Renal Impairment
Plasma concentrations may increase following IV administration of chloramphenicol sodium succinate to patients with renal impairment, probably due to decreased renal clearance of the succinate ester. Chloramphenicol is only slightly dialyzable, and neither hemodialysis nor peritoneal dialysis alter serum concentrations to an extent requiring dose adjustments or supplemental dosing. Monitor serum drug concentration closely.