VA Class:AM150

AHFS Class:

• Chloramphenicol 8:12.08

Generic Name(s):

• Chloramphenicol Sodium Succinate

Molecular Formula:

• C₁₅H₁₅Cl₂N₂NaO₈

Chloramphenicol is a broad-spectrum antibacterial agent.104,110,112

Chloramphenicol must be used only for the treatment of serious infections caused by susceptible bacteria or Rickettsia when potentially less toxic anti-infectives are contraindicated or ineffective.112 The drug must not be used for the treatment of trivial infections or when it is not indicated (e.g., treatment of colds, influenza, throat infections) and must not be used as a prophylactic agent to prevent bacterial infections.112

Prior to initiation of chloramphenicol therapy, appropriate specimens should be collected for identification of the causative organism and in vitro susceptibility tests.112 Chloramphenicol may be started pending results of in vitro susceptibility testing, but the drug should be discontinued as soon as possible if results indicate that the causative organism is resistant to chloramphenicol or if the organism is found to be susceptible to potentially less toxic anti-infectives.112 If results of in vitro susceptibility testing indicate that chloramphenicol and another anti-infective are both likely to be effective, a decision to continue use of chloramphenicol rather than switching to the other anti-infective should be based on the severity of the infection, comparative in vitro susceptibility of the drugs, expected efficacy of the drugs in the specific infection, and comparative safety profiles of the drugs.112

Meningitis

Chloramphenicol is used as an alternative for the treatment of meningitis caused by susceptible bacteria, including susceptible Haemophilus influenzae ,110,112,418 Neisseria meningitidis ,110,418 or Streptococcus pneumoniae .110,418 Chloramphenicol is not considered a drug of first choice for the treatment of meningitis and generally is used only when penicillins and cephalosporins are contraindicated or ineffective.101,102,104,105,110,197,418 Despite evidence of in vitro activity against Listeria monocytogenes , chloramphenicol has been ineffective for the treatment of systemic infections caused by this organism.475 Chloramphenicol should not be used for the treatment of meningitis caused by gram-negative bacilli.475

Pending results of CSF culture and in vitro susceptibility testing, the most appropriate anti-infective regimen for empiric treatment of suspected bacterial meningitis should be selected based on results of CSF gram stain and antigen tests, age of the patient, the most likely pathogen(s) and source of infection, and current patterns of bacterial resistance within the hospital and local community.145,146,148,292,418,475 When results of culture and susceptibility tests become available and the pathogen is identified, the empiric anti-infective regimen should be modified (if necessary) to ensure that the most effective regimen is being administered.145,148,418,475

Although chloramphenicol has been recommended as an alternative to penicillins and third generation cephalosporins for the treatment of meningitis caused by susceptible β-lactamase-producing or non-β-lactamase-producing H. influenzae ,418,475 strains of chloramphenicol-resistant H. influenzae have been reported in some areas of the world and this limits use of the drug, including for empiric treatment when H. influenzae may be involved.104,110,125,418,475 There also is some evidence that third generation cephalosporins are as effective or more effective than chloramphenicol for the treatment of meningitis caused by susceptible H. influenzae .418,475

IV penicillin G, ampicillin, and third generation cephalosporins usually are considered the drugs of choice for the treatment of meningitis caused by N. meningitidis ,146,292,418,475 and chloramphenicol is recommended as one of several alternatives when penicillins and cephalosporins cannot be used.197,292,418 Strains of N. meningitidis resistant to chloramphenicol have been reported.142

Chloramphenicol has been used as an alternative to penicillins and third generation cephalosporins for the treatment of meningitis caused by penicillin-susceptible S. pneumoniae .418,475 However, treatment failures have been reported when chloramphenicol was used in the treatment of infections caused by penicillin-resistant S. pneumoniae , despite the fact that in vitro susceptibility tests indicated that the clinical isolates were susceptible to chloramphenicol.110,475

Rickettsial Infections

Chloramphenicol has been used for the treatment of rickettsial infections and has been recommended as a possible alternative to tetracyclines in certain situations.104,110,112,197,292,500,525,526,529,530 The US Centers for Disease Control and Prevention (CDC) and other experts state that doxycycline is the drug of choice for the treatment of all rickettsial infections in all age groups (including children younger than 8 years of age).292,500,525 These experts state that empiric treatment with a tetracycline (preferably doxycycline) should be initiated immediately in patients with known or suspected rickettsial disease and should not be delayed while waiting for confirmatory testing since some of these infections can be rapidly progressive and may be fatal or lead to long-term sequelae.292,500,525 If an alternative to doxycycline is being considered for the treatment of a rickettsial infection, CDC recommends consultation with an expert.525

Rocky Mountain Spotted Fever and Other Tickborne Spotted Fevers

CDC and the American Academy of Pediatrics (AAP) state that doxycycline is the drug of choice for the treatment of all tickborne rickettsial infections, including Rocky Mountain spotted fever (RMSF) caused by Rickettsia rickettsii , regardless of patient age.292,500,525 Chloramphenicol has been recommended as a possible alternative to doxycycline for the treatment of RMSF in patients who have had potentially life-threatening allergic reactions to the drug (e.g., anaphylaxis, Stevens-Johnson syndrome) and in pregnant women.292,500,525,530 However, there is some epidemiologic evidence that the risk of death in patients with RMSF is higher in those treated with chloramphenicol than in those treated with a tetracycline and close monitoring is required if chloramphenicol is used.292,500,527 CDC states that the risks and benefits of chloramphenicol versus doxycycline in patients with a history of allergic reactions to tetracyclines should be considered for the individual patient.500 For those with a history of non-life-threatening reactions to tetracyclines, CDC states that administering doxycycline in an observed setting is a possible option.500 Although data are limited, CDC states that rapid doxycycline desensitization in consultation with an allergy and immunology specialist may be an option for individuals with a history of life-threatening hypersensitivity reactions to tetracyclines.500

CDC states that, although chloramphenicol is a potential alternative to doxycycline for the treatment of RMSF in pregnant women, chloramphenicol must be used with caution during the third trimester of pregnancy because of the theoretical risk of gray syndrome (see Cautions: Gray Syndrome).500

Endemic, Epidemic, and Scrub Typhus

Chloramphenicol has been recommended as a possible alternative to doxycycline for the treatment of endemic typhus (murine typhus; fleaborne typhus) caused by R. typhi or R. felis ,197,292,529,530 but may be less effective than doxycycline.292 Doxycycline is the drug of choice for the treatment of endemic typhus, regardless of patient age.292

Chloramphenicol has been recommended as a possible alternative to doxycycline for the treatment of epidemic typhus (louseborne typhus; sylvatic typhus) caused by R. prowazekii (e.g., in patients with life-threatening allergic reactions to doxycycline).197,292,529,530 Doxycycline is the drug of choice for the treatment of epidemic typhus, regardless of patient age.292

Although chloramphenicol has been used for the treatment of scrub typhus caused by Orientia tsutsugamushi 110,178,197,526 and is recommended as a possible alternative to doxycycline for the treatment of such infections,197,526,529 chloramphenicol resistance and persistence or relapse of the infection has been reported.110,178

Anaplasmosis and Ehrlichiosis

Chloramphenicol should not be used for the treatment of anaplasmosis caused by Anaplasma phagocytophilum (also known as human granulocytic anaplasmosis; HGA) or ehrlichiosis caused by Ehrlichia chaffeensis (also known as human monocytic ehrlichiosis; HME).159,500 CDC and other experts state that doxycycline is the drug of choice for the treatment of human ehrlichiosis and anaplasmosis, regardless of patient age.159,292,500

Although chloramphenicol has been used in some patients for the treatment of ehrlichiosis† caused by E. chaffeensis or E. canis and was recommended in the past as a possible alternative to tetracyclines for these infections,159,160,197 such use is not supported by results of in vitro susceptibility testing for these organisms and the drug is considered ineffective for these infections.159,500

Typhoid Fever and Other Severe Salmonella Infections

Chloramphenicol has been used for the treatment of typhoid fever (enteric fever) caused by susceptible Salmonella enterica serovar Typhi.104,110,112,134,136,139,140,173,174,175,183,197 The drug also has been used for the treatment of paratyphoid fever caused by S. enterica serovar Paratyphi.110,140,174

Various anti-infectives have been used for the treatment of typhoid fever, including ampicillin, amoxicillin, chloramphenicol, co-trimoxazole, cefotaxime, ceftriaxone, fluoroquinolones, and azithromycin.134,139,150,151,174,175,183,197,292 Although chloramphenicol was a drug of choice for the treatment of infections caused by typhoidal Salmonella in the past,104,173,175,183 multidrug-resistant strains of S. enterica serovar Typhi (i.e., strains resistant to ampicillin, chloramphenicol, and/or co-trimoxazole) are reported worldwide and are common in many regions of the world.173,175,183,292 In addition, strains with decreased susceptibility or resistance to other drugs used for the treatment of typhoid fever (e.g., fluoroquinolones, third generation cephalosporins) have been reported.173,175 Whenever possible, anti-infectives for the treatment of typhoid fever should be selected based on results of in vitro susceptibility testing.175,292 For empiric treatment of typhoid fever known or likely to be caused by multidrug-resistant strains, azithromycin or a parenteral third generation cephalosporin (e.g., ceftriaxone, cefotaxime) has been recommended.173,292

Chloramphenicol should not be used for the treatment of typhoid carriers.104,110,112 Depending on susceptibility of the strain, a fluoroquinolone (e.g., ciprofloxacin), ampicillin, amoxicillin, or co-trimoxazole usually is recommended to treat the typhoid carrier state.173,175,197,292

Chloramphenicol should not be used for the treatment of uncomplicated Salmonella gastroenteritis.104,110

Anthrax

Chloramphenicol has been recommended as an alternative for the treatment of anthrax†.104,668,670,671,672,673,680,683 Although there is evidence that chloramphenicol has in vitro activity against Bacillus anthracis ,161,668 limited clinical data exist regarding use of the drug in the treatment of anthrax.668,680

Penicillins generally have been considered the drugs of choice for the treatment of anthrax (inhalational, GI, meningitis) caused by penicillin-susceptible B. anthracis that occurs as the result of natural or endemic exposures, although a fluoroquinolone (e.g., ciprofloxacin) or doxycycline also has been recommended for the treatment of naturally occurring anthrax.670,680 A multiple-drug regimen may be indicated in patients with severe infections.670,680 Chloramphenicol has been suggested as an alternative for the treatment of naturally occurring anthrax in patients hypersensitive to penicillins or as one of several options for use in multiple-drug regimens for the treatment of anthrax;670 however, the World Health Organization (WHO) states that chloramphenicol is no longer recommended as an alternative for the treatment of naturally occurring anthrax because evidence of in vivo efficacy in the treatment of severe anthrax is lacking and the drug is associated with serious adverse effects.680

For the treatment of inhalational anthrax that occurs as the result of exposure to B. anthracis spores in the context of biologic warfare or bioterrorism, CDC, AAP, and the US Working Group on Civilian Biodefense recommend that treatment be initiated with a multiple-drug parenteral regimen that includes a fluoroquinolone (preferably ciprofloxacin) or doxycycline and 1 or 2 additional anti-infective agents predicted to be effective.668,671,672,673,683 Based on in vitro data, drugs that have been suggested as possibilities to augment ciprofloxacin or doxycycline in such multiple-drug regimens include clindamycin, rifampin, a carbapenem (doripenem, imipenem, meropenem), chloramphenicol, vancomycin, penicillin, ampicillin, linezolid, gentamicin, and clarithromycin.668,671,672,673,683 IV anti-infective therapy is recommended for initial treatment of clinically apparent GI, inhalational, septicemic, or meningeal anthrax and also is indicated for the treatment of cutaneous anthrax when there are signs of systemic involvement, extensive edema, or head and neck lesions.668,671,672

For the treatment of systemic anthrax with possible or confirmed meningitis, CDC and AAP recommend a regimen of IV ciprofloxacin with an IV bactericidal anti-infective (preferably meropenem) and an IV protein synthesis inhibitor (preferably linezolid).671,672,673 These experts state that IV chloramphenicol is a possible alternative to linezolid in this regimen, but should be used only if clindamycin and rifampin are not available.671,672,673

Burkholderia Infections

Burkholderia cepacia Infections

Chloramphenicol has been used in patients with cystic fibrosis112 and has been recommended as an alternative for the treatment of infections caused by Burkholderia cepacia † (formerly Ps. cepacia ).197 However, B. cepacia usually is resistant to chloramphenicol in vitro.104,110

Patients with cystic fibrosis often are chronically infected or colonized with species within the B. cepacia complex.157,158,177,292 In addition, the B. cepacia complex has been associated with infections in immunocompromised patients (e.g., those with chronic granulomatous disease, hemoglobinopathies, malignant neoplasms) and in preterm infants.157,158,292 Optimum regimens for the treatment of chronic B. cepacia complex infections have not been identified and anti-infectives should be selected based on in vitro susceptibility data and previous clinical responses.177 Anti-infectives that have been recommended for the treatment of these infections include meropenem, imipenem, co-trimoxazole, ceftazidime, doxycycline, and chloramphenicol;292 some experts recommend that multiple-drug regimens be used.292

Melioidosis

Chloramphenicol has been used in conjunction with doxycycline and co-trimoxazole for the treatment of melioidosis†, a life-threatening disease caused by B. pseudomallei (formerly Ps. pseudomallei );154,176,197 however, chloramphenicol is not usually recommended.104,110 B. pseudomallei is an aerobic, nonfermentative gram-negative bacilli resistant to many anti-infectives.155 The drugs of choice for the treatment of melioidosis depend on the type of infection, results of in vitro susceptibility tests, and the presence of comorbidities (e.g., diabetes mellitus, liver or renal disease, malignancies, hemoglobinopathies, cystic fibrosis).292 Many clinicians recommend ceftazidime or a carbapenem (either meropenem or imipenem) as the drugs of choice for initial treatment of severe melioidosis,104,110,152,153,154,156,180,197,292 followed by long-term treatment with an oral anti-infective (e.g., co-trimoxazole, amoxicillin and clavulanate potassium, doxycycline) given for at least 3 months to reduce the risk of relapse.104,180,292 There is some evidence that ceftazidime monotherapy has been associated with a lower mortality rate than a 3-drug regimen of IV chloramphenicol, oral doxycycline, and oral co-trimoxazole.153,154 In addition, there is evidence that a 2-drug oral regimen of co-trimoxazole and doxycycline is as effective and better tolerated for follow-up treatment than a 3-drug oral regimen of co-trimoxazole, doxycycline, and chloramphenicol (oral preparation no longer available in the US).176 B. pseudomallei may be difficult to eradicate, and relapse of melioidosis may occur, especially if there is poor compliance with the follow-up regimen.104,152,153,154,156,180

Plague

Chloramphenicol is used as an alternative for the treatment of plague† caused by Yersinia pestis .133,197,292,683,688,690

Streptomycin (or gentamicin) historically has been considered the drug of choice for the treatment of plague.104,197,292,683,688,690 Alternatives recommended when these aminoglycosides are not used include fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), doxycycline (or tetracycline), chloramphenicol, or co-trimoxazole (may be less effective than other alternatives).104,292,683,688,690 Chloramphenicol is considered a drug of choice for the treatment of plague meningitis.104,292,683

Anti-infective regimens recommended for the treatment of naturally occurring or endemic bubonic, septicemic, or pneumonic plague also are recommended for the treatment of plague that occurs following exposure to Y. pestis in the context of biologic warfare or bioterrorism.683,688 Such exposures would most likely result in primary pneumonic plague,688 and prompt initiation of anti-infective therapy (within 18-24 hours of onset of symptoms) is essential in the treatment of pneumonic plague.683,688 Some experts (e.g., the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases [USAMRIID]) recommend that treatment of plague in the context of biologic warfare or bioterrorism be initiated with a parenteral anti-infective regimen of streptomycin (or gentamicin) or, alternatively, doxycycline, a fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin), or chloramphenicol.683,688 An oral regimen of doxycycline (or tetracycline) or a fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin) may be substituted when the patient's condition improves or when parenteral therapy is unavailable (e.g., when there are supply or logistic problems because large numbers of individuals require treatment in a mass casualty setting).688 Although oral chloramphenicol has been recommended as an alternative in these situations,688 an oral preparation of chloramphenicol is no longer commercially available in the US.

In the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense, USAMRIID) recommend that asymptomatic individuals with exposure to plague aerosol or asymptomatic individuals with household, hospital, or other close contact (within about 2 m) with an individual who has pneumonic plague receive an oral anti-infective for postexposure prophylaxis; however, any exposed individual who develops a temperature of 38.5°C or higher or new cough should promptly receive a parenteral anti-infective for treatment of the disease.683,688 If postexposure prophylaxis is indicated, these experts recommend an oral regimen of doxycycline (or tetracycline) or a fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin).683,688 Although oral chloramphenicol has been recommended as an alternative for postexposure prophylaxis following exposure to Y. pestis in the context of biologic warfare or bioterrorism,683,688 an oral preparation of chloramphenicol is no longer commercially available in the US.

Tularemia

Chloramphenicol is used as an alternative for the treatment of tularemia† caused by Francisella tularensis .133,197,683,689

Streptomycin generally has been considered the drug of choice for the treatment of tularemia; however, gentamicin is more readily available and is considered an alternative drug of choice when streptomycin is unavailable.104,197,292,683,689 Alternatives recommended for the treatment of tularemia when these aminoglycosides are not used include tetracyclines (doxycycline), chloramphenicol, or ciprofloxacin.197,292,683,689 Some clinicians state that chloramphenicol should be reserved for the treatment of tularemic meningitis (usually used in conjunction with streptomycin),104,683 and should not be used for other forms of tularemia.104

Anti-infective regimens recommended for the treatment of naturally occurring or endemic tularemia also are recommended for the treatment of tularemia that occurs following exposure to F. tularensis in the context of biologic warfare or bioterrorism.683,689 However, the fact that a fully virulent streptomycin-resistant strain of F. tularensis was developed in the past for use in biologic warfare should be considered.683,689 Exposures to F. tularensis in the context of biologic warfare or bioterrorism would most likely result in inhalational tularemia with pleuropneumonitis, although the organism also can infect humans through the skin, mucous membranes, and GI tract.689

Reconstitution and Administration

Chloramphenicol sodium succinate is administered IV.112

Although chloramphenicol has been administered IM†,104,108,110,113 plasma concentrations following IM injection are unpredictable.104 The manufacturer states that chloramphenicol sodium succinate should not be given IM since the drug may be ineffective when administered by this route.112

Chloramphenicol has been administered orally as the base or as chloramphenicol palmitate;104,110 however, oral preparations of the drug are no longer commercially available in the US.

IV Administration

Prior to IV administration, chloramphenicol sodium succinate vials labeled as containing 1 g of chloramphenicol should be reconstituted by adding 10 mL of aqueous diluent (e.g., sterile water for injection, 5% dextrose injection) to provide a solution containing 100 mg of chloramphenicol per mL.112

Rate of Administration

The appropriate dose of reconstituted chloramphenicol solution should be injected IV over a period of at least 1 minute.112,301

The drug also has been given by intermittent IV infusion† over 15-60 minutes.55,104,110,301

Dosage

Dosage of chloramphenicol sodium succinate is expressed in terms of chloramphenicol.112

Because the difference between therapeutic and toxic plasma concentrations of chloramphenicol is narrow (i.e., a narrow therapeutic index) and because of interindividual differences in chloramphenicol metabolism and elimination, most clinicians recommend that plasma concentrations of chloramphenicol be monitored in all patients receiving the drug and dosage adjusted accordingly.101,102,104,105,107,108,109,110,112,114,115,179,184,301 Blood samples to measure peak plasma concentrations of chloramphenicol usually are obtained 0.5-1.5 hours after an IV dose.179,184,301

Chloramphenicol dosage generally should be adjusted to maintain plasma concentrations of 5-20 mcg/mL (usually 10-20 mcg/mL).101,102,104,105,107,108,110,179 When used in pediatric patients beyond the neonatal period, the American Academy of Pediatrics (AAP) suggests that chloramphenicol dosage be adjusted to maintain target plasma concentrations of 15-25 mcg/mL.292 Some clinicians suggest that dosage in pediatric patients be adjusted to maintain peak plasma concentrations of 15-25 mcg/mL for the treatment of meningitis or 10-20 mcg/mL for the treatment of other infections.184 Chloramphenicol plasma concentrations greater than 25 mcg/mL have been associated with toxicity.104,179

Chloramphenicol should be used no longer than is necessary to eradicate the infection with little or no risk of relapse.112 IV chloramphenicol should be switched to an appropriate oral anti-infective as soon as feasible.112

Repeated courses of chloramphenicol should be avoided if possible.112

Pediatric Dosage

General Dosage for Neonates

The manufacturer states that an IV chloramphenicol dosage of 25 mg/kg daily given in 4 equally divided doses every 6 hours usually provides and maintains blood and tissue concentrations of the drug that are adequate for most indications.112 The manufacturer also states that, after the first 2 weeks of life, full-term neonates usually may receive a dosage up to 50 mg/kg daily given in 4 equally divided doses every 6 hours.112 If a higher dosage is required for the treatment of severe infections in neonates, the manufacturer recommends that such dosage be given only to maintain blood concentrations within a therapeutically effective range.112

Some clinicians recommend that neonates receive an IV loading dose of chloramphenicol of 20 mg/kg followed 12 hours later by maintenance dosage based on age and weight.184 These clinicians recommend a maintenance dosage of 25 mg/kg once every 24 hours in neonates 7 days of age or younger, 25 mg/kg once every 24 hours in neonates older than 7 days of age weighing 2 kg or less, and 25 mg/kg once every 12 hours in those older than 7 days of age weighing more than 2 kg.184

Other clinicians recommend that neonates receive an IV loading dose of 20 mg/kg followed 12 hours later by maintenance dosage based on age and weight.301 These clinicians recommend that premature neonates weighing 1.2 kg or less receive a maintenance dosage of 22 mg/kg once every 24 hours and that premature neonates 1 week of age or younger weighing 2 kg or less receive a maintenance dosage of 25 mg/kg once every 24 hours.301 These clinicians recommend that full-term neonates younger than 2 weeks of age receive a maintenance dosage of 25 mg/kg daily in divided doses every 12 hours and that full-term neonates 2-4 weeks of age receive a maintenance dosage of 25-50 mg/kg daily in divided doses every 12 hours.301

Chloramphenicol should be used with caution in neonates because immature metabolic processes in this age group may result in excessive plasma concentrations of the drug.112 (See Cautions: Pediatric Precautions.)

General Dosage for Pediatric Patients Beyond the Neonatal Period

The manufacturer states that an IV chloramphenicol dosage of 50 mg/kg daily given in 4 divided doses every 6 hours provides blood concentrations of the drug that are adequate for most indications in pediatric patients.112 For the treatment of severe infections (e.g., bacteremia, meningitis), especially when adequate CSF concentrations are desired, the manufacturer states that a dosage up to 100 mg/kg daily may be required;112 however, this dosage should be reduced to 50 mg/kg daily as soon as possible.112

If IV chloramphenicol is used for the treatment of severe infections in pediatric patients beyond the neonatal period, AAP recommends a dosage of 50-100 mg/kg daily given in 4 divided doses.292

General Dosage for Pediatric Patients with Immature Metabolic Processes

The manufacturer states that IV chloramphenicol given in a dosage of 25 mg/kg daily will usually produce therapeutic blood concentrations of the drug in young infants and other pediatric patients in whom immature metabolic functions are suspected.112

Chloramphenicol plasma concentrations should be carefully monitored in patients with immature metabolic processes because high concentrations of the drug may occur and tend to increase with succeeding doses.112 (See Cautions: Pediatric Precautions.)

Rickettsial Infections

If IV chloramphenicol is used as an alternative for the treatment of rickettsial infections, including Rocky Mountain spotted fever (RMSF) in children, a dosage of 12.5-25 mg/kg every 6 hours for 5-10 days has been recommended.526,530

In patients with known or suspected RMSF, anti-infective treatment should be initiated promptly and should be continued for at least 3 days after fever subsides and until there is evidence of clinical improvement.292,500 The minimum duration of treatment is 5-7 days;292,500 a longer duration may be required for severe or complicated disease.500

When considering use of chloramphenicol for the treatment of rickettsial infections, consultation with an expert is recommended.525 (See Uses: Rickettsial Infections.)

Typhoid Fever and other Severe Salmonella Infections

For the treatment of typhoid fever, pediatric patients 14 years of age or older have received IV chloramphenicol in a dosage of 50 mg/kg daily in 4 divided doses (up to 3 g daily) for 14 days.140 In children 2 years of age or older with typhoid fever, the drug has been given in a dosage of 60 mg/kg daily until defervescence, followed by 40 mg/kg daily to complete 14 days of treatment.134

To lessen the possibility of relapse, some clinicians recommend that chloramphenicol dosage be adjusted to provide therapeutic plasma concentrations of the drug and treatment be continued for 8-10 days after the patient becomes afebrile.112

Anthrax

If IV chloramphenicol is used as an alternative for the treatment of anthrax† (inhalational, GI, meningitis) that occurs as the result of natural or endemic exposures to Bacillus anthracis (see Uses: Anthrax), some clinicians recommend that children receive a dosage of 50-75 mg/kg daily given in divided doses every 6 hours.670 Treatment of naturally occurring or endemic anthrax generally should be continued for at least 14 days after symptoms abate.670

If IV chloramphenicol is used as an alternative in a multiple-drug regimen for initial treatment of severe anthrax† (inhalational, GI, meningitis, or cutaneous with systemic involvement, extensive edema, or head or neck lesions) that occurs in the context of biologic warfare or bioterrorism, AAP recommends that full-term or preterm neonates 7 days of age or younger receive IV chloramphenicol in a dosage of 25 mg/kg once daily and that those 1-4 weeks of age receive 50 mg/kg daily in divided doses every 12 hours.671 AAP recommends that children 1 month of age or older receive IV chloramphenicol in a dosage of 100 mg/kg daily in divided doses every 6 hours.671 The multiple-drug parenteral regimen should be continued for at least 2-3 weeks until the patient is clinically stable;671 treatment can then be switched to appropriate oral anti-infectives.671

Plague

If IV chloramphenicol is used as an alternative for the treatment of pneumonic plague† that occurs as the result of exposure to Yersinia pestis in the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense) recommend that children 2 years of age or older receive a dosage of 25 mg/kg 4 times daily and that dosage be adjusted to maintain plasma chloramphenicol concentrations of 5-20 mcg/mL.688 Other experts (e.g., US Army Medical Research Institute of Infectious Diseases [USAMRIID]) recommend that children 2 years of age or older receive an IV loading dose of 25 mg/kg followed by 15 mg/kg IV every 6 hours and that dosage be adjusted based on plasma concentrations.683

Treatment can be switched to an appropriate oral anti-infective when clinically indicated;688 the total duration of treatment usually is 10-14 days.683,688,690

Tularemia

If IV chloramphenicol is used as an alternative for the treatment of tularemia† that occurs as the result of exposure to Francisella tularensis in the context of biologic warfare or bioterrorism, some experts (e.g., US Working Group on Civilian Biodefense) recommend that children receive a dosage of 15 mg/kg 4 times daily.689 Treatment can be switched to an appropriate oral anti-infective when clinically indicated;689 the total duration of treatment usually is 14-21 days.689

If IV chloramphenicol is used in conjunction with streptomycin (or gentamicin) for the treatment of tularemic meningitis in children, some clinicians recommend a dosage of 15 mg/kg every 6 hours (maximum 4 g daily) given for 14-21 days.104

Adult Dosage

General Dosage for Adults

The manufacturer recommends that adults with normal renal and hepatic function receive an IV chloramphenicol dosage of 50 mg/kg daily given in divided doses every 6 hours.112

In infections caused by less susceptible organisms, the manufacturer states that an IV chloramphenicol dosage up to 100 mg/kg daily may be required.112 However, because toxic plasma concentrations of the drug may occur in many patients receiving dosages of 100 mg/kg daily, some clinicians suggest that a dosage of 75 mg/kg daily be used initially for the treatment of such infections.102,105 Dosage should be reduced to 50 mg/kg daily as soon as possible.112

Rickettsial Infections

If IV chloramphenicol is used as an alternative for the treatment of rickettsial infections, including endemic typhus or epidemic typhus, in adults, a dosage of 60-75 mg/kg daily in 4 divided doses for 5-10 days has been recommended.526,530 For the treatment of scrub typhus caused by Orientia tsutsugamushi , a dosage of 50-100 mg/kg daily (up to 3 g daily) in divided doses every 6 hours has been recommended.526

In patients with known or suspected RMSF, anti-infective treatment should be initiated promptly and should be continued for at least 3 days after fever subsides and until there is evidence of clinical improvement.500 The minimum duration of treatment is 5-7 days;500 a longer duration may be required for severe or complicated disease.500

When considering use of chloramphenicol for the treatment of a rickettsial infection, consultation with an expert is recommended.525 (See Uses: Rickettsial Infections.)

Typhoid Fever and Other Salmonella Infections

For the treatment of typhoid fever in adults, IV chloramphenicol has been given in a dosage of 50 mg/kg daily in 4 divided doses for 14 days.140 The drug also has been given in a dosage of 60 mg/kg daily in 4 divided doses until defervescence followed by 40 mg/kg daily in 4 divided doses to complete 14 days of treatment.134

To lessen the possibility of relapse, some clinicians recommend that chloramphenicol be given in a dosage that provides therapeutic plasma concentrations of the drug and treatment be continued for 8-10 days after the patient becomes afebrile.112

Anthrax

If IV chloramphenicol is used as an alternative in a multiple-drug regimen for the treatment of anthrax† (inhalational, GI, meningitis) that occurs as the result of natural or endemic exposures to B. anthracis (see Uses: Anthrax), some clinicians recommend that adults receive a dosage of 50-100 mg/kg daily given in divided doses every 6 hours.670 Treatment of naturally occurring or endemic anthrax generally should be continued for at least 14 days after symptoms abate.670

If IV chloramphenicol is used as an alternative in a multiple-drug regimen for initial treatment of severe anthrax† (inhalational, GI, meningitis, or cutaneous with systemic involvement, extensive edema, or head or neck lesions) that occurs in the context of biologic warfare or bioterrorism, the US Centers for Disease Control and Prevention (CDC) recommends that adults receive a dosage of 1 g every 6-8 hours.672,673 The multiple-drug parenteral regimen should be continued for at least 2-3 weeks until the patient is clinically stable; treatment can then be switched to appropriate oral anti-infectives.672,673

Plague

If IV chloramphenicol is used as an alternative for the treatment of pneumonic plague† that occurs as the result of exposure to Y. pestis in the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense) recommend that adults receive a dosage of 25 mg/kg 4 times daily and that dosage be adjusted to maintain plasma chloramphenicol concentrations of 5-20 mcg/mL.688 Other experts (e.g., USAMRIID) recommend an IV loading dose of 25 mg/kg followed by 15 mg/kg IV every 6 hours and that dosage be adjusted based on plasma concentrations.683

Treatment can be switched to an appropriate oral anti-infective when clinically indicated;688 total duration of treatment usually is 10-14 days.683,688,690

Tularemia

If IV chloramphenicol is used as an alternative for the treatment of tularemia† that occurs as the result of exposure to F. tularensis in the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense) recommend that adults receive a dosage of 15 mg/kg 4 times daily.689 Other experts (e.g., USAMRIID) recommend a dosage of 15-25 mg/kg IV every 6 hours.683 Treatment can be switched to an appropriate oral anti-infective when clinically indicated;689 the total duration of treatment usually is 14-21 days.689

If IV chloramphenicol is used in conjunction with streptomycin (or gentamicin) for the treatment of tularemic meningitis, some clinicians recommend that adults receive a dosage of 15-25 mg/kg every 6 hours (maximum 4 g daily) given for 14-21 days.104

Dosage in Renal and Hepatic Impairment

Because patients with renal and/or hepatic impairment may have reduced ability to metabolize and eliminate chloramphenicol,112 dosage should be based on plasma chloramphenicol concentrations and adjusted accordingly.110,112,301

Clinicians should consider that pediatric patients with impaired renal or hepatic function may retain excessive amounts of the drug.112 (See General Dosage for Pediatric Patients with Immature Metabolic Processes under Dosage: Pediatric Dosage, in Dosage and Administration.)

Hematologic Effects

Serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) have occurred in patients receiving both short-term and prolonged treatment with chloramphenicol.112 Aplastic anemia attributed to chloramphenicol, which later terminated in leukemia, has been reported.112

Two forms of hematologic toxicity may occur with chloramphenicol.104,110,112 The first type is the most common and is a dose-related bone marrow suppression that appears to be a direct pharmacologic effect of chloramphenicol and usually is reversible upon discontinuance of the drug.104,110,112 This type of bone marrow suppression is characterized by anemia, leukopenia, reticulocytopenia, thrombocytopenia, increased concentrations of serum iron, increased serum iron-binding capacity, and vacuolation of erythroid and myeloid precursors.104,112 It is more likely to occur in patients receiving a chloramphenicol dosage of 4 g daily or higher and in those with plasma chloramphenicol concentrations greater than 25 mcg/mL.104

The second type of hematologic toxicity that can occur in patients receiving chloramphenicol is a rare, but often fatal, irreversible aplastic anemia that does not appear to be dose related.104,110,112 This type of bone marrow effect leading to aplastic anemia has been reported with oral or parenteral chloramphenicol and has been associated with a mortality rate greater than 50%.104,110 Bone marrow aplasia or hypoplasia may occur weeks or months after the drug has been discontinued.112 Pancytopenia is frequently observed peripherally, but in some cases only 1 or 2 of the major cell types (erythrocytes, leukocytes, platelets) may be depressed.112

Paroxysmal nocturnal hemoglobinuria has been reported in patients receiving chloramphenicol.112 Hemolytic anemia has been reported when chloramphenicol was used in patients with glucose-6-phosphate dehydrogenase deficiency.104,110

Gray Syndrome

A type of circulatory collapse, referred to as the gray syndrome, has occurred in neonates and premature infants receiving chloramphenicol.104,110,112 In most cases, chloramphenicol therapy had been instituted within the first 48 hours of life; however, the gray syndrome has occurred in older infants and in infants born to mothers who received chloramphenicol during the late stages of pregnancy or during labor.110,112 In addition, a similar syndrome has been reported in older children and adults following chloramphenicol overdosage.104,110

Symptoms of the gray syndrome in infants usually develop 2-9 days after chloramphenicol therapy is initiated and include abdominal distention (with or without vomiting), progressive pallid cyanosis, flaccidity, and vasomotor collapse which may frequently be accompanied by irregular respiration.104,110,112 Gray syndrome can be fatal within a few hours after onset of symptoms.112 However, if chloramphenicol is discontinued when early evidence of symptoms becomes apparent, the process may be reversible and complete recovery may follow.112

The gray syndrome may occur because chloramphenicol impairs myocardial contractility by directly interfering with myocardial tissue respiration and oxidative phosphorylation.104,110 It has been attributed to high plasma concentrations of chloramphenicol and is believed to occur more frequently in neonates and young infants because of their inability to conjugate chloramphenicol and excrete the unconjugated drug.104,110,112

Nervous System Effects

Optic neuritis,104,110,112 rarely resulting in optic atrophy and blindness,104,110 has been reported in patients receiving chloramphenicol, usually following long-term therapy with the drug.104,110,112 Although symptoms tend to be reversible, permanent vision loss may occur.104,110

Peripheral neuritis has occurred following long-term chloramphenicol therapy.104,110,112 Headache,104,110,112 ophthalmoplegia,104,110 depression,104,110,112 confusion,104,110,112 and delirium110,112 have been reported.

GI and Hepatic Effects

Adverse GI effects, including nausea,110,112 vomiting,110,112 diarrhea,110,112 glossitis,110,112 stomatitis,110,112 and enterocolitis112 have been reported rarely with chloramphenicol.112

Sensitivity Reactions

Hypersensitivity reactions, including anaphylaxis,112 rash (macular and vesicular),112 angioedema,112 urticaria,112 and fever,112 have occurred in patients receiving chloramphenicol.

Herxheimer-like reactions have occurred in patients receiving chloramphenicol for the treatment of typhoid fever.112

Precautions and Contraindications

Chloramphenicol is contraindicated in patients with a history of hypersensitivity and/or toxic reactions to the drug.112

Because serious, sometimes fatal, reactions have been reported in patients who received chloramphenicol, patients should be hospitalized during therapy with the drug so that appropriate laboratory studies and clinical observations can be made.112 Chloramphenicol must not be used for the treatment of trivial infections or when it is not indicated (e.g., treatment of colds, influenza, throat infections) and must not be used for prophylaxis.112 The drug should be administered no longer than is necessary to eradicate the infection with little or no risk of relapse, and repeated courses should be avoided if possible.112

Because of the narrow margin between effective therapeutic and toxic dosages of chloramphenicol and because there are interindividual differences in metabolism and elimination of the drug, most clinicians recommend that plasma concentrations of chloramphenicol be monitored in all patients receiving the drug.101,102,104,105,107,108,109,114,115 In general, plasma chloramphenicol concentrations should be maintained at 5-20 mcg/mL to ensure efficacy and avoid toxicity.101,102,104,105,107,108 (See Dosage and Administration: Dosage.)

It is essential that adequate hematologic studies be performed prior to and approximately every 2 days during chloramphenicol therapy.112 The drug should be discontinued if reticulocytopenia, leukopenia, thrombocytopenia, anemia, or other hematologic abnormalities attributable to chloramphenicol occur.112 Although peripheral blood studies may detect leukopenia, reticulocytopenia, or granulocytopenia before these become irreversible, such studies cannot be relied on to detect bone marrow depression prior to development of aplastic anemia.112

If optic or peripheral neuritis occurs during chloramphenicol therapy (see Cautions: Nervous System Effects), the drug should be discontinued immediately.112

Chloramphenicol should be used with caution in patients with impaired renal and/or hepatic function and in neonates and infants or other pediatric patients with immature metabolic processes.112 Plasma chloramphenicol concentrations should be monitored closely in these patients and dosage should be adjusted accordingly.110,112

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.112 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.112

As with other anti-infectives, use of chloramphenicol may result in overgrowth of nonsusceptible organisms, including fungi.112 If infection caused by nonsusceptible organisms occurs, appropriate therapy should be instituted.112

Pediatric Precautions

Chloramphenicol should be used with caution in premature and full-term neonates and infants to avoid potential toxicity, including a type of circulatory collapse referred to as the gray syndrome.112 (See Cautions: Gray Syndrome.)

Excessive plasma concentrations of chloramphenicol may occur in neonates and infants or other pediatric patients with immature metabolic processes, even when recommended chloramphenicol dosage is used.104,110,112 Plasma concentration of the drug should be determined at appropriate intervals during chloramphenicol treatment and dosage should be adjusted accordingly.112 (See Dosage and Administration: Dosage.)

Geriatric Precautions

Clinical studies of chloramphenicol did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric adults respond differently than younger patients.112 Other reported clinical experience has not identified differences in responses between geriatric and younger adults.112

Chloramphenicol is substantially eliminated by the kidneys, and the risk of adverse effects may be greater in those with impaired renal function.112 Dosage in geriatric patients should be selected with caution, usually starting at the low end of the dosage range, and it may be useful to monitor renal function during chloramphenicol treatment.112 The greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients should be considered.112

Mutagenicity and Carcinogenicity

Animal and human studies have not been performed to evaluate the mutagenic and carcinogenic potential of chloramphenicol.112

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies evaluating use of chloramphenicol in pregnant women.112 Animal reproduction studies have not been conducted using the drug.112

Studies using oral chloramphenicol (no longer commercially available in the US) indicate that the drug crosses the placenta.110,112

Use of chloramphenicol during late pregnancy and during labor has been associated with the gray syndrome and other adverse effects in the fetus or infant.110,112 (See Cautions: Gray Syndrome.)

Because of potential toxic effects on the fetus, the manufacturer states that chloramphenicol should be used during pregnancy only if potential benefits justify potentials risks to the fetus.112

Fertility

Animal and human studies have not been performed to evaluate whether chloramphenicol affects fertility.112

Lactation

Studies using oral chloramphenicol (no longer commercially available in the US) indicate that the drug is distributed into human milk.112

Because chloramphenicol potentially could cause serious adverse effects in breast-fed infants (see Cautions: Gray Syndrome), the manufacturer states that a decision should be made whether to discontinue nursing or chloramphenicol, taking into account the importance of the drug to the woman.112

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Chloramphenicol inhibits cytochrome P-450 (CYP) isoenzymes 2C9 and 3A4.104,110

Antianemia Drugs

When administered concurrently with iron preparations, vitamin B₁₂, or folic acid, chloramphenicol may delay the response to these drugs.104,110

Anticoagulants

Chloramphenicol may prolong the half-life of warfarin.104

Anticonvulsants

Concomitant use of fosphenytoin and chloramphenicol may result in altered (increased or decreased) chloramphenicol concentrations.104

Concomitant use of phenobarbital and chloramphenicol has resulted in decreased plasma concentrations of chloramphenicol.58,59,104 Concomitant use of the drugs may increase clearance of chloramphenicol resulting in a 30-40% reduction in plasma concentrations of the drug.104 In addition, phenobarbital plasma concentrations may be increased by up to 50%.104

Concomitant use of phenytoin and chloramphenicol may result in altered (increased or decreased) chloramphenicol concentrations and may result in potentially toxic plasma chloramphenicol concentrations.104,110 In addition, concomitant use of the drugs may increase plasma concentrations and prolong the half-life of phenytoin resulting in phenytoin toxicity.104,110

Antidiabetic Agents

Chloramphenicol may decrease metabolism of some sulfonylurea antidiabetic agents (e.g., chlorpropamide, tolbutamide) and may increase plasma half-lives of these drugs.104,110

Anti-infective Agents

Chloramphenicol has been reported to antagonize the bactericidal activity of certain penicillins, cephalosporins, fluoroquinolones, and aminoglycosides in vitro.104,110 Although the clinical importance of this in vitro data is unclear,110 some clinicians recommend that chloramphenicol and these anti-infectives be used concomitantly with caution104 or that concomitant use be avoided.110

Results of an in vitro study using Klebsiella pneumoniae indicate that chloramphenicol can antagonize the bactericidal activity of aztreonam.116 It has been suggested that if concomitant use of the drugs is indicated, chloramphenicol should be administered a few hours after aztreonam; however, the necessity of this precaution has not been established.116

Concomitant use of chloramphenicol and rifampin may increase clearance of chloramphenicol resulting in decreased plasma concentrations of the drug.103,110

Cyclophosphamide

Concomitant use of cyclophosphamide and chloramphenicol may prolong the half-life of cyclophosphamide and result in decreased concentrations of the active cyclophosphamide metabolite and reduced effectiveness of the drug.104

Immunosuppressive Agents

Concomitant use of cyclosporine and chloramphenicol may result in increased cyclosporine concentrations and increased risk of renal dysfunction, cholestasis, and paresthesias.104

Concomitant use of tacrolimus and chloramphenicol may result in increased tacrolimus concentrations.104

Myelosuppressive Agents

Because of potential additive effects on bone marrow, concomitant use of chloramphenicol and other drugs associated with bone marrow depression should be avoided.112

Typhoid Vaccine

Concomitant use of chloramphenicol and typhoid vaccine live oral Ty21a may decrease efficacy of the live, attenuated vaccine.104

Mechanism of Action

Chloramphenicol usually is bacteriostatic in action,104,110,112 but may be bactericidal against some organisms.104,110

Chloramphenicol inhibits protein synthesis in susceptible organisms by reversibly binding to the peptidyl transferase cavity of the 50S ribosomal subunit of the bacterial 70S ribosome.104,110 This prevents the aminoacyl-tRNA from binding to the ribosome and terminates polypeptide chain synthesis.104

Chloramphenicol also appears to inhibit protein synthesis in rapidly proliferating mammalian cells.26,29,110 It has been suggested that dose-related bone marrow depression due to chloramphenicol is the result of inhibition of protein synthesis in mitochondria of bone marrow cells.29,104,110,181

Spectrum

Chloramphenicol has a broad spectrum of activity and is active in vitro against many gram-positive and gram-negative aerobic bacteria, some anaerobic bacteria, and some other organisms, including some Rickettsia , Chlamydia , and Mycoplasma .104,110,112 The drug is inactive against Mycobacterium 104,110 and protozoa.104,110

Gram-positive Bacteria

Chloramphenicol is active in vitro against many gram-positive aerobic cocci, including Staphylococcus aureus ,104,110 S. epidermidis ,110 Streptococcus pneumoniae ,110 S. pyogenes (group A β-hemolytic streptococci; GAS),110 S. agalactiae (group B streptococci; GBS),110α-hemolytic streptococci,110 and Enterococcus faecalis .110 Chloramphenicol may be active in vitro against some methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) and some S. aureus resistant to vancomycin.104,110

Chloramphenicol also is active in vitro against some other gram-positive bacteria, including Corynebacterium diphtheriae 104,110 and Listeria monocytogenes .104,110 The drug is not active against Nocardia .104,110

Chloramphenicol has in vitro activity against Bacillus anthracis .104,110,161,167,668 Results of in vitro susceptibility testing of 11 B. anthracis isolates that were associated with cases of inhalational or cutaneous anthrax that occurred in the US (Florida, New York, District of Columbia) during September and October 2001 in the context of an intentional release of anthrax spores (biologic warfare, bioterrorism) indicate that these strains had chloramphenicol MICs of 4 mcg/mL and were considered susceptible to the drug.167 Limited clinical data are available to date regarding in vivo activity of chloramphenicol against B. anthracis or use of the drug in the treatment of anthrax.167,668,680

Gram-negative Bacteria

Chloramphenicol is active in vitro against some gram-negative aerobic bacteria, including Haemophilus influenzae ,104,110,112 H. parainfluenzae ,110 Moraxella catarrhalis ,104,110 Neisseria gonorrhoeae ,104 and N. meningitidis .104

Although chloramphenicol is active against some Enterobacteriaceae, including some Citrobacter , Enterobacter , Escherichia coli , Hafnia , Klebsiella , Proteus , Providencia , Salmonella , and Shigella , susceptibility is variable and many strains are resistant to the drug.104,110

Yersinia pestis 110,171,172 and Y. enterocolitica 110 usually are susceptible to chloramphenicol, but resistant strains have been reported.110

Burkholderia pseudomallei generally is susceptible to chloramphenicol.104,110B. cepacia and Pseudomonas aeruginosa usually are resistant to the drug.104,110

Chloramphenicol usually is active against Aeromonas ,110 Bordetella pertussis ,110 Brucella ,110 Campylobacter jejuni ,110 Francisella tularensis ,691 Helicobacter pylori ,110 Legionella pneumophila ,110 Pasteurella multocida ,110 and Vibrio parahaemolyticus .110 Although V. cholerae usually are susceptible to chloramphenicol, resistance has been reported.110

Anaerobic Bacteria

Chloramphenicol is active in vitro against many gram-positive anaerobic bacteria, including Actinomyces ,110 Bifidobacterium ,110 Clostridium ,104,110 Eubacterium ,110 Lactobacillus ,104,110 Peptococcus ,110 Peptostreptococcus ,104 and Propionibacterium .104,110

Chloramphenicol also is active in vitro against some gram-negative anaerobic bacteria, including Bacteroides fragilis ,104,110 Fusobacterium ,104,110 Prevotella ,104,110 and Veillonella .104,110

Other Organisms

Treponema pallidum , Chlamydia , and Mycoplasma are susceptible to chloramphenicol.110

Chloramphenicol is active against some Rickettsia , including R. rickettsii and causative agents of various typhus fevers.110 The drug also is active against Coxiella burnetii .110

In Vitro Susceptibility Testing

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), clinical isolates identified as susceptible to chloramphenicol are inhibited by drug concentrations usually achievable when the recommended dosage is used for the site of infection.137 Clinical isolates classified as intermediate have minimum inhibitory concentrations (MICs) that approach usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.137 Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a higher than usual dosage can be used.137 This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.137 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to chloramphenicol, the strain is not inhibited by drug concentrations generally achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and clinical efficacy of the drug against the isolate has not been reliably demonstrated in clinical studies.137

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to chloramphenicol, a disk containing 30 mcg/mL of the drug should be used.137

When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures using CLSI interpretive criteria, Staphylococcus or Enterococcus with growth inhibition zones of 18 mm or greater are susceptible to chloramphenicol, those with zones of 13-17 mm have intermediate susceptibility, and those with zones of 12 mm or less are resistant to the drug.137

When the disk-diffusion procedure is performed according to CLSI standardized procedures, Haemophilus with growth inhibition zones of 29 mm or greater are susceptible to chloramphenicol, those with zones of 26-28 mm have intermediate susceptibility, and those with zones of 25 mm or less are resistant to the drug.137

When testing susceptibility of S. pneumoniae according to CLSI standardized procedures, S. pneumoniae with growth inhibition zones of 21 mm or greater are susceptible to chloramphenicol and those with zones of 20 mm or less are resistant to the drug.137 When testing streptococci other than S. pneumoniae , those with zones of 21 mm or greater are susceptible to chloramphenicol, those with zones of 18-20 mm have intermediate susceptibility, and those with zones of 17 mm or less are resistant to the drug.137

When the disk-diffusion procedure is performed according to CLSI standardized procedures, N. meningitidis with growth inhibition zones of 26 mm or greater are susceptible to chloramphenicol, those with zones of 20-25 mm have intermediate susceptibility, and those with zones of 19 mm or less are resistant to the drug.137

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to CLSI standardized procedures, Staphylococcus , Enterococcus , Enterobacteriaceae, non-Enterobacteriaceae gram-negative bacilli (e.g., B. cepacia complex, Pseudomonas spp. other than Ps. aeruginosa ) with MICs of 8 mcg/mL or less are susceptible to chloramphenicol, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug.137

When broth dilution susceptibility testing is performed according to CLSI standardized procedures, Haemophilus or N. meningitidis with MICs of 2 mcg/mL or less are susceptible to chloramphenicol, those with MICs of 4 mcg/mL have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater are resistant to the drug.137

When testing susceptibility of S. pneumoniae according to CLSI standardized procedures, S. pneumoniae with MICs of 4 mcg/mL or less are susceptible to chloramphenicol and those with MICs of 8 mcg/mL or greater are resistant to the drug.137 Streptococci other than S. pneumoniae with MICs of 4 mcg/mL or less are susceptible to chloramphenicol, those with MICs of 8 mcg/mL have intermediate susceptibility, and those with MICs of 16 mcg/mL or greater are resistant to the drug.137

When broth dilution susceptibility testing is performed according to CLSI standardized procedures, anaerobes with MICs of 8 mcg/mL or less are susceptible to chloramphenicol, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug.137

Resistance

Resistance to chloramphenicol has been induced in vitro and has been shown to be induced in a stepwise manner. The reported incidence of chloramphenicol resistance in clinical isolates varies considerably worldwide and may be reported more frequently in regions of the world where the drug is still commonly used and has not been reserved for the treatment of serious infections.104,110

Several mechanisms of resistance to chloramphenicol have been reported.104 A common mechanism of resistance to the drug is enzymatic acetylation and inactivation by chloramphenicol acetyltransferases (CATs).104,110 CATs have been identified in many different bacteria and may be readily transmitted to other bacteria.110 Other mechanisms of resistance to chloramphenicol involve transmembrane efflux pumps, decreased membrane permeability, or alterations in the 50S ribosomal subunit.104,110

Staphylococcus aureus ,104,110S. epidermidis ,110S. hemolyticus ,110Streptococcus pneumoniae ,104,110,126,131S. pyogenes ,110 and Enterococcus faecium 110 resistant to chloramphenicol have been reported.

Escherichia coli , Salmonella , and Shigella resistant to chloramphenicol have been reported with increasing frequency.110 Chloramphenicol-resistant strains of Haemophilus influenzae 104,110,125 and Neisseria meningitidis 110,142 have been reported rarely.

Clostridium difficile and C. perfringens resistant to chloramphenicol have been reported.104

Pharmacokinetics

Absorption

Following IV administration of chloramphenicol sodium succinate, there is considerable interindividual variation in plasma chloramphenicol concentrations attained in adults, children, or neonates.101,102,107,109,110,114 (For information on monitoring plasma chloramphenicol concentrations, see Dosage and Administration: Dosage.) Chloramphenicol sodium succinate is a prodrug and is hydrolyzed in vivo to active chloramphenicol.102,107,110 The rate and extent of hydrolysis of the ester are highly variable.101,102,107,109,110,114 Bioavailability of chloramphenicol following IV administration of chloramphenicol sodium succinate also depends on renal clearance of the unchanged ester, which also is highly variable.102,107,110

Distribution

Chloramphenicol is widely distributed into body tissues and fluids including ascitic fluid, pleural fluid, synovial fluid, saliva, and aqueous and vitreous humor.104,107,110,112 Highest concentrations of the drug are found in the liver and kidneys.112

Chloramphenicol is distributed into CSF, even in the absence of meningeal inflammation.55,104,110,112 CSF concentrations of chloramphenicol have been reported to be at least 50% of concurrent plasma concentrations in patients with uninflamed meninges.104,110,112 In 3 neonates 2-6 weeks of age receiving IV chloramphenicol for the treatment of meningitis or ventriculitis, CSF concentrations of the drug were 45-89% of concurrent plasma concentrations.55

Chloramphenicol crosses the placenta.104,107,110,112

Chloramphenicol is distributed into milk.104,107,110,112

Chloramphenicol is approximately 60% bound to plasma proteins.107

Elimination

Chloramphenicol sodium succinate is hydrolyzed in vivo, presumably by esterases in the liver, kidneys, and lungs, to form active chloramphenicol.102,107,110 Chloramphenicol is then metabolized primarily in the liver to chloramphenicol glucuronide, an inactive metabolite.104,110

Following IV administration of chloramphenicol sodium succinate in adults with normal renal and hepatic function, approximately 30% of the dose is excreted unchanged in urine;102,107 however, the fraction of the dose excreted unchanged in urine varies considerably and may range from 6-80%.102,107,109,110 Small amounts of the dose (2-3%) are eliminated in bile and about 1% is eliminated in feces.104,110

The plasma half-life of chloramphenicol in adults with normal renal and hepatic function is 1.2-4.1 hours.101,104,107,110

Because neonates and premature infants have immature mechanisms for glucuronide conjugation and renal excretion,107,110,112 usual doses of chloramphenicol may produce high and prolonged plasma concentrations of the drug in such neonates and infants.110,112 The plasma half-life of chloramphenicol is inversely related to age.110 In one study, plasma half-life was 10-36 hours in neonates 1-8 days of age and 5.5-15.7 hours in infants 11 days to 8 weeks of age.110

The elimination half-life of chloramphenicol is prolonged and clearance of the drug is decreased in patients with reduced hepatic function.107,110

In patients with impaired renal function, the elimination half-life of chloramphenicol is not significantly prolonged,107 although accumulation of the inactive conjugated metabolite may occur.110 Following IV administration of chloramphenicol sodium succinate in patients with renal impairment, plasma chloramphenicol concentrations may be increased since renal excretion of the succinate ester is reduced in these patients.107

Increased chloramphenicol clearance has been reported in patients undergoing hemodialysis.110 Plasma half-life of chloramphenicol is not affected by peritoneal dialysis.110,182 The drug appears to be readily removed by charcoal hemoperfusion.100

Chemistry and Stability

Chemistry

Chloramphenicol is a broad-spectrum antibiotic originally isolated from Streptomyces venezuelae and now produced synthetically.112 Chloramphenicol occurs as fine, white to grayish or yellowish white, needle-like crystals or elongated plates, has a solubility of approximately 2.5 mg/mL in water at 25°C, and is freely soluble in alcohol. The pK_a of the drug is 5.5. Chloramphenicol sodium succinate occurs as a white to light yellow powder and is freely soluble in water and in alcohol.

Chloramphenicol sodium succinate is commercially available as a lyophilized powder that should be reconstituted as directed by the manufacturer to provide an IV solution containing 100 mg of chloramphenicol per mL.112 Each 1 g of chloramphenicol in the reconstituted solution contains approximately 52 mg (2.25 mEq) of sodium.112

Stability

Chloramphenicol sodium succinate powder for injection should be stored at 20-25°C.112

Chloramphenicol has been reported to be physically incompatible with some drugs, but the compatibility depends on several factors (e.g., the concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.300

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