Chloramphenicol, Chloramphenicol Sodium Succinate
Chloramphenicol is a synthetic antibiotic that is active in vitro against many gram-positive and -negative aerobic bacteria.
Uses
Chloramphenicol should be used only for the treatment of serious infections caused by susceptible bacteria or Rickettsia when potentially less toxic drugs are ineffective or contraindicated. The drug must not be used for the treatment of trivial infections, as a prophylactic agent to prevent bacterial infections, or when it is not indicated as in the treatment of colds, influenza, or throat infections. Prior to initiation of chloramphenicol therapy, appropriate specimens should be collected for identification of the causative organism and in vitro susceptibility tests. Chloramphenicol therapy may be started pending results of susceptibility tests, but the drug should be discontinued if tests show the causative organism to be resistant to chloramphenicol or if the organism is found to be susceptible to potentially less toxic drugs.
Typhoid Fever and Other Salmonella Infections
Chloramphenicol is used in the treatment of typhoid fever (enteric fever) caused by susceptible Salmonella typhi. Various anti-infectives have been used for the treatment of typhoid fever, including chloramphenicol, ampicillin, amoxicillin, co-trimoxazole, cefotaxime, ceftriaxone, fluoroquinolones, and azithromycin.
Multidrug-resistant strains of S. typhi (i.e., strains resistant to ampicillin, chloramphenicol, and/or co-trimoxazole) have been reported with increasing frequency, and a third generation cephalosporin (e.g., ceftriaxone, cefotaxime) or a fluoroquinolone (e.g., ciprofloxacin, ofloxacin) are considered the drugs of first choice for the treatment of typhoid fever or other severe infections known or suspected to be caused by these strains. Although the time to defervescence in typhoid fever reportedly is faster with chloramphenicol therapy than with ampicillin therapy, results of a few controlled studies indicate that the response time is slower with chloramphenicol than with amoxicillin.
There is some evidence that up to 10% of patients who receive chloramphenicol for the treatment of typhoid fever become temporary or permanent carriers of S. typhi. Amoxicillin, co-trimoxazole, or a fluoroquinolone (e.g., ciprofloxacin) generally are the drugs of choice to treat the typhoid carrier state; chloramphenicol should not be used to treat S. typhi carriers.
Meningitis
Chloramphenicol is used for the treatment of meningitis caused by susceptible bacteria, including susceptible strains of Neisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae. However, 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.
Chloramphenicol should not be used for the treatment of meningitis caused by gram-negative bacilli and, despite evidence of in vitro activity against Listeria monocytogenes, the drug usually is ineffective for the treatment of meningitis caused by this organism.
While IV ampicillin used in conjunction with IV chloramphenicol previously was considered a regimen of choice for empiric treatment of meningitis in children and infants 1 month of age or older, most clinicians now recommend an empiric regimen of IV ampicillin and either IV ceftriaxone or IV cefotaxime in this age group.
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.
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.
Chloramphenicol is used as an alternative to penicillins and cephalosporins for the treatment of meningitis caused by penicillin-susceptible S. pneumoniae. 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.
It has been suggested that chloramphenicol may have had only bacteriostatic activity in these patients, and the drug probably should be used in the treatment of meningitis caused by penicillin-resistant S. pneumoniae only if results of in vitro tests indicate that the minimum bactericidal concentration (MBC) of chloramphenicol for the clinical isolate involved is 4 mcg/mL or less. Because there are insufficient data regarding efficacy of chloramphenicol given in conjunction with other anti-infectives for the treatment of meningitis caused by penicillin-resistant S. pneumoniae, the American Academy of Pediatrics (AAP) states that such regimens cannot be recommended for these infections.
For information on treatment of meningitis caused by S. pneumoniae, including strains with reduced susceptibility to penicillins and/or cephalosporins, see Meningitis Caused by Streptococcus pneumoniae under Uses: Meningitis and Other CNS Infections in Ceftriaxone 8:12.06.
Chloramphenicol can be used as an alternative to penicillins and cephalosporins for the treatment of meningitis caused by b-lactamase-producing or non-b-lactamase-producing H. influenzae. While strains of chloramphenicol- resistant H. influenzae have been reported in some areas of the world, these strains are relatively rare in the US. While many clinicians suggest a regimen of ceftriaxone or cefotaxime for the initial treatment of meningitis caused by H. influenzae, the AAP suggests that children with meningitis possibly caused by H. influenzae also could receive an initial treatment regimen of ampicillin given in conjunction with chloramphenicol.
The incidence of H. influenzae meningitis in the US has decreased considerably since H. influenzae type b conjugate vaccines became available for immunization of infants. Although IV penicillin G is considered the drug of choice for the treatment of meningitis caused by N. meningitidis and ceftriaxone or cefotaxime the preferred alternatives, especially for penicillin-resistant strains, chloramphenicol is considered an alternative to penicillins and cephalosporins for the treatment of N. meningitidis meningitis.Strains of N. meningitidis resistant to chloramphenicol have been isolated from some meningitis patients in some areas of the world (e.g., Vietnam, France) and may be a concern in developing countries where chloramphenicol routinely is used for the treatment of meningococcal meningitis.
Anthrax
Chloramphenicol is used as an alternative agent in the treatment of anthrax. Parenteral penicillins generally have been considered the drugs of choice for the treatment of naturally occurring or endemic anthrax caused by susceptible Bacillus anthracis, including clinically apparent GI, inhalational, or meningeal anthrax and anthrax septicemia, although IV ciprofloxacin or IV doxycycline also are recommended.
Chloramphenicol is suggested as an alternative to penicillin G for use in patients hypersensitive to penicillins, especially for the treatment of anthrax meningoencephalitis. 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, the US Centers for Disease Control and Prevention (CDC) and the US Working Group on Civilian Biodefense recommend that treatment be initiated with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline and 1 or 2 other anti-infective agents predicted to be effective.
Based on in vitro data, drugs that have been suggested as possibilities to augment ciprofloxacin or doxycycline in such multiple-drug regimens include chloramphenicol, clindamycin, rifampin, vancomycin, clarithromycin, imipenem, penicillin, or ampicillin. If meningitis is established or suspected, some clinicians suggest a multiple-drug regimen that includes ciprofloxacin (rather than doxycycline) and chloramphenicol, rifampin, or penicillin.
There is evidence that chloramphenicol has in vitro activity against B. anthracis; however, limited or no clinical data exist regarding use of the drug in the treatment of anthrax and efficacy has not been evaluated in human or animal studies. IV anti-infective therapy is recommended for the initial treatment of clinically apparent GI, inhalational, or meningeal anthrax and anthrax septicemia and also is indicated for the treatment of cutaneous anthrax when there are signs of systemic involvement, extensive edema, or head and neck lesions. For additional information on treatment of anthrax and recommendations for prophylaxis following exposure to anthrax spores, see Uses: Anthrax, in Ciprofloxacin 8:12.18.
Rickettsial Infections
Although tetracyclines generally are the drugs of choice for the treatment of Rocky Mountain spotted fever and other rickettsial infections, chloramphenicol is the drug of choice for rickettsial infections when tetracyclines cannot be used. Chloramphenicol generally is considered the drug of choice for the treatment of rickettsial infections in children younger than 8 years of age and in pregnant women (see Cautions: Pregnancy and Lactation) since tetracyclines should be avoided in these patients; however, some clinicians suggest that the risk of serious, sometimes fatal, adverse effects associated with chloramphenicol therapy be weighed against the risk of tetracycline therapy (e.g., discoloration of teeth) in these patients.
Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections
Chloramphenicol has been used in the treatment of orofacial, intra-abdominal, or soft-tissue anaerobic bacterial infections, but generally is used in these infections only when other appropriate anti-infectives (e.g., metronidazole, clindamycin) are contraindicated or ineffective. Some clinicians suggest that chloramphenicol can be used as an alternative in the treatment of infections caused by Clostridium perfringens, Fusobacterium, or Bacteroides when the drugs of first choice and other less toxic alternatives cannot be used.
Cholera
Chloramphenicol has been used as an adjunct to fluid and electrolyte replacement in the treatment of cholera (Vibrio cholerae). While tetracyclines are considered the drugs of choice for anti-infective treatment of cholera, fluoroquinolones, furazolidone, co-trimoxazole, or chloramphenicol are considered alternative agents.
Burkholderia Infections Melioidosis
Chloramphenicol is used in conjunction with doxycycline and co-trimoxazole for the treatment of melioidosis, a life-threatening disease caused by Burkholderia pseudomallei (formerly Ps. pseudomallei). B. pseudomallei is an aerobic, nonfermentative gram-negative bacilli resistant to many anti-infective agents. Ceftazidime monotherapy is considered by many clinicians to be the drug of choice for the treatment of severe melioidosis, and has been associated with a lower mortality rate than a 3-drug regimen of IV chloramphenicol, oral doxycycline, and oral co-trimoxazole.
Other drugs that have been recommended as alternative agents for the treatment of melioidosis include amoxicillin and clavulanate potassium, imipenem, or meropenem. B. pseudomallei is difficult to eradicate, and relapse of melioidosis commonly occurs. Therefore, anti-infective therapy usually is continued for 6 weeks to 6 months or, alternatively, a parenteral anti-infective (e.g., ceftazidime) is given for at least 1-2 weeks followed by an oral anti-infective (e.g., amoxicillin and clavulanate potassium) given for at least 3-6 months.
Glanders
Some clinicians suggest that chloramphenicol and streptomycin can be used as an alternative to tetracycline and streptomycin for the treatment of glanders caused by B. mallei (formerly Ps. mallei).
Burkholderia cepacia Infections
Some clinicians suggest that chloramphenicol can be used for the treatment of infections caused by Burkholderia cepacia (formerly Ps. cepacia). Patients with cystic fibrosis often are colonized with B. cepacia (with or without Ps. aeruginosa colonization). In addition, B. cepacia recently has been recognized as a cause of nosocomial pneumonia in immunocompromised patients. B. cepacia is an aerobic, nonfermentative gram-negative bacilli resistant to many anti-infective agents, and no anti-infective regimen has been identified that effectively eradicates the organism in colonized cystic fibrosis patients. Some clinicians consider co-trimoxazole the drug of choice and ceftazidime, chloramphenicol, and imipenem alternative agents for the treatment of B. cepacia infections.
Plague
Chloramphenicol is used as an alternative agent for the treatment of plague caused by Yersinia pestis. Streptomycin (or gentamicin) generally is considered the drug of choice for the treatment of plague. Alternative drugs recommended when aminoglycosides are not used including doxycycline (or tetracycline), chloramphenicol, or co-trimoxazole (may be less effective than other alternatives); based on results of in vitro and animal testing, ciprofloxacin (or another fluoroquinolone) also is recommended as an alternative. Chloramphenicol generally is considered the drug of choice for the treatment of plague meningitis. 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.
These exposures would most likely result in primary pneumonic plague. Prompt initiation of anti-infective therapy (within 18-24 hours of onset of symptoms) is essential in the treatment of pneumonic plague. Some experts (e.g., the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend that treatment of plague in the context of biologic warfare or bioterrorism should be initiated with a parenteral anti-infective regimen of streptomycin (or gentamicin) or, alternatively, doxycycline, ciprofloxacin, or chloramphenicol, although an oral regimen (doxycycline, ciprofloxacin) may be substituted when the patient’s condition improves or if parenteral therapy is unavailable.
Postexposure prophylaxis with anti-infectives is recommended after high-risk exposures to plague, including close exposure to individuals with naturally occurring plague or laboratory exposure to viable Y. pestis. In the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) 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 postexposure anti-infective prophylaxis; however, any exposed individual who develops a temperature of 38.°C or higher or new cough should promptly receive a parenteral anti-infective for treatment of the disease. An oral regimen of doxycycline or ciprofloxacin usually is recommended for such prophylaxis.
Although some experts suggest that oral chloramphenicol can be used as an alternative for postexposure prophylaxis following exposure to Y. pestis in the context of biologic warfare or bioterrorism, an oral preparation of chloramphenicol is no longer commercially available in the US.
Tularemia
Chloramphenicol is used as an alternative to streptomycin (or gentamicin) for the treatment of tularemia caused by Francisella tularensis. Other alternatives include tetracyclines (doxycycline) or ciprofloxacin. Gentamicin may be as effective as streptomycin, but clinical relapse occurs frequently in tularemia patients treated with tetracyclines or chloramphenicol.
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. 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.
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. For information on postexposure prophylaxis of tularemia, including prophylaxis following exposures in the context of biologic warfare or bioterrorism, see Uses: Tularemia, in the Tetracyclines General Statement 8:12..
Brucellosis
For the treatment of brucellosis, some clinicians suggest that a regimen of chloramphenicol (with or without streptomycin) can be used as an alternative to a tetracycline regimen when the tetracycline regimen cannot be used; however, the AAP suggests that a regimen of co-trimoxazole (with or without rifampin) be used for the treatment of brucellosis in children younger than 8 years of age who cannot receive a tetracycline.
Ehrlichiosis
Chloramphenicol has been used in some patients for the treatment of ehrlichiosis caused by Ehrlichia chaffeensis or E. canis. While some clinicians suggest that chloramphenicol can be used as an alternative agent for the treatment of E. chaffeensis infections when tetracyclines are contraindicated, other clinicians suggest that efficacy of chloramphenicol for these infections has not been established. 159 The AAP states that a comparison of the benefits and risks of a single short course of tetracycline for the treatment of ehrlichiosis in a child younger than 8 years of age with the benefits and risks of chloramphenicol justifies the use of doxycycline in these patients, especially since an oral preparation of chloramphenicol is no longer commercially available in the US.
The manufacturer states that the usual IV dosage of chloramphenicol for neonates and children in whom immature hepatic and/or renal function is suspected is 25 mg/kg daily. The American Academy of Pediatrics (AAP) recommends that children and infants 1 month of age or older receive a dosage of 50-100 mg/kg daily given in 4 divided doses for the treatment of severe infections. If chloramphenicol is used for the treatment of meningitis or other severe infection caused by Streptococcus pneumoniae, the AAP recommends that children and infants 1 month of age or older receive a dosage of 75-100 mg/kg daily given in divided doses every 6 hours. For ophthalmic uses of chloramphenicol, see 52:04.04.
Dosage and Administration
Reconstitution and Administration
Chloramphenicol sodium succinate is administered IV. Although chloramphenicol sodium succinate has been administered IM, most clinicians recommend the drug not be administered IM since it may be less effective when administered by this route.
Chloramphenicol has been administered orally as the base or as chloramphenicol palmitate; however, oral preparations of the drug no longer are commercially available in the US. For IV administration, chloramphenicol sodium succinate is reconstituted by adding 10 mL of an aqueous diluent (e.g., sterile water for injection, 5% dextrose injection) to a vial labeled as containing 1 g of chloramphenicol to provide a solution containing 100 mg of chloramphenicol per mL; the calculated dose should be injected over a period of at least 1 minute.
Dosage
Dosage of chloramphenicol sodium succinate is expressed in terms of chloramphenicol. Because the difference between therapeutic and toxic plasma concentrations of chloramphenicol is narrow 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. In general, chloramphenicol dosage should be adjusted to maintain plasma concentrations at 5-20 mcg/mL.
Chloramphenicol should be administered no longer than is necessary to eradicate the infection with little or no risk of relapse, and repeated courses of therapy should be avoided if possible.
General Dosage
The usual IV dosage of chloramphenicol for adults and children with normal renal and hepatic function is 50 mg/kg daily given in equally divided doses every 6 hours. In infections caused by less susceptible organisms, or if necessary in order to achieve adequate CSF concentrations, up to 100 mg/kg daily may be required; however, because toxic plasma chloramphenicol concentrations may occur in many patients with dosages of 100 mg/kg daily, some clinicians suggest that a dosage of 75 mg/kg daily be used initially in the treatment of these infections.
Dosage should be reduced to 50 mg/kg daily as soon as possible. The manufacturer states that the usual IV dosage of chloramphenicol for neonates and children in whom immature hepatic and/or renal function is suspected is 25 mg/kg daily. The American Academy of Pediatrics (AAP) recommends that children and infants 1 month of age or older receive a dosage of 50-100 mg/kg daily given in 4 divided doses for the treatment of severe infections. If chloramphenicol is used for the treatment of meningitis or other severe infection caused by Streptococcus pneumoniae, the AAP recommends that children and infants 1 month of age or older receive a dosage of 75-100 mg/kg daily given in divided doses every 6 hours.
Typhoid Fever
For the treatment of typhoid fever in adults and children, chloramphenicol usually is given in a dosage of 50 mg/kg daily in divided doses every 6 hours for 14-15 days.
Anthrax
When chloramphenicol is used as an alternative for the treatment of anthrax, some clinicians suggest that adults receive IV chloramphenicol in a dosage of 50-100 mg/kg daily given in 4 divided doses and that children receive 50-75 mg/kg daily given in 4 divided doses for the treatment of clinically apparent GI, inhalational, or meningeal anthrax or anthrax septicemia. For the treatment of anthraxmeningoencephalitis, some clinicians suggest that IV chloramphenicol be given in a dosage of 1 g every 4 hours. Although anti-infective therapy of these infections usually is continued for at least 2 weeks after symptoms abate, some clinicians suggest that anti-infective treatment of clinically apparent inhalational or cutaneous anthrax be continued for 60 days if anthrax occurred as the result of exposure to anthrax spores in the context of biologic warfare or bioterrorism.
Plague
If chloramphenicol is used 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 adults and children 2 years of age or older receive IV chloramphenicol in a dosage of 25 mg/kg 4 times daily for 10 days. If chloramphenicol is used for the treatment of plague meningitis, some experts recommend an IV loading dose of 25 mg/kg followed by 15 mg/kg IV 4 times daily for 10-14 days.
Although an oral preparation of chloramphenicol is not commercially available in the US, some experts suggest that adults and children 2 years of age or older can receive oral chloramphenicol in a dosage of 25 mg/kg 4 times daily for 7 days for postexposure prophylaxis following exposure to Y. pestis in the context of biologic warfare or bioterrorism. Tularemia If chloramphenicol is used for the treatment of tularemia that occurs as the result of exposure to Francisella tularensis in the context of biologic warfare or bioterrorism, the US Working Group on Civilian Biodefense recommends that adults and children receive IV chloramphenicol in a dosage of 15 mg/kg 4 times daily for 14-21 days.
Dosage in Renal and Hepatic Impairment
In patients with impaired renal and/or hepatic function, dosage of chloramphenicol must be reduced in proportion to the degree of impairment and should be based on plasma chloramphenicol concentrations.
Cautions
Hematologic Effects
One of the most serious adverse effects of chloramphenicol is bone marrow depression. Although rare, blood dyscrasias such as aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia have occurred during or following both short-term and prolonged therapy.
Hemolytic anemia has occurred rarely with chloramphenicol, and paroxysmal nocturnal hemoglobinuria has also been reported. In addition, there have been reports of aplastic anemia which later terminated in leukemia. Two forms of bone marrow depression may occur with chloramphenicol.
The first type is nondose-related, irreversible bone marrow depression leading to aplastic anemia with a 50% or greater mortality rate, generally resulting from hemorrhage or infection. Bone marrow aplasia or hypoplasia may occur after a single dose of chloramphenicol, but more often develops weeks or months after the drug has been discontinued. Pancytopenia is frequently observed peripherally, but in some cases only 1 or 2 of the major cell types (erythrocytes, leukocytes, platelets) may be depressed.
The second and more common type of bone marrow depression is dose related and usually reversible upon discontinuance of chloramphenicol. This type of bone marrow depression is characterized by anemia, vacuolation of erythroid cells, reticulocytopenia, leukopenia, thrombocytopenia, increased concentrations of serum iron, and increased serum iron-binding capacity.
Reversible bone marrow depression occurs regularly when plasma concentrations of active chloramphenicol are 25 mcg/mL or greater or when chloramphenicol dosage in adults exceeds 4 g daily.
Gray Syndrome
A type of circulatory collapse, referred to as the gray syndrome, has occurred in premature and newborn infants receiving chloramphenicol. In most cases, chloramphenicol therapy had been instituted within the first 48 hours of life; however, the gray syndrome has occurred in children as old as 2 years of age and in infants born to mothers who received chloramphenicol during the final stages of pregnancy or labor.
Symptoms of the gray syndrome usually develop 2-9 days after the start of chloramphenicol therapy and include failure to feed, abdominal distention with or without vomiting, progressive pallid cyanosis, and vasomotor collapse which may be accompanied by irregular respiration. Death may occur within a few hours. If chloramphenicol is discontinued when early evidence of symptoms becomes apparent, the process may be reversible and complete recovery may follow. The gray syndrome has been attributed to high concentrations of the drug which result from the inability of infants to conjugate chloramphenicol or excrete the unconjugated drug.
Nervous System Effects
Optic neuritis, rarely resulting in blindness, has been reported following long-term high-dose chloramphenicol therapy. Ocular symptoms usually include bilateral diminution of visual acuity and central scotomas. Peripheral neuritis has also occurred following long-term chloramphenicol therapy. If optic or peripheral neuritis occurs, chloramphenicol should be discontinued immediately. Other neurotoxic reactions that have been reported occasionally with chloramphenicol are headache, mental depression, confusion, and delirium.
GI and Hepatic Effects
Adverse GI effects including nausea, vomiting, diarrhea, unpleasant taste, glossitis, stomatitis, pruritus ani, and enterocolitis occur infrequently with chloramphenicol. Rarely, jaundice has been reported.
Sensitivity Reactions
Hypersensitivity reactions have occurred and may be manifested by fever; macular and vesicular rashes; angioedema; urticaria; hemorrhage of the skin and mucosal and serosal surfaces of the intestine, bladder, and mouth; and anaphylactoid reactions. Herxheimer-like reactions have occurred in patients receiving chloramphenicol for the treatment of typhoid fever and may be due to the release of bacterial endotoxins.
Precautions and Contraindications
Serious, sometimes fatal, reactions have been reported in patients who received chloramphenicol. Patients should be hospitalized during chloramphenicol therapy so that appropriate laboratory studies and clinical observations can be made.
Because of the narrow margin between effective therapeutic and toxic dosages of chloramphenicol and because there are wide variations in chloramphenicol bioavailability depending on the route of administration, dosage form, and 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. In general, plasma chloramphenicol concentrations should be maintained at 5-20 mcg/mL to ensure efficacy and avoid toxicity.
Hematologic studies should be performed prior to and approximately every 2 days during chloramphenicol therapy. The drug should be discontinued if reticulocytopenia, leukopenia, thrombocytopenia, anemia, or other hematologic abnormalities attributable to chloramphenicol occur. Peripheral blood studies cannot be relied upon to predict the occurrence of irreversible bone marrow depression and aplastic anemia. If optic or peripheral neuritis occurs during chloramphenicol therapy, the drug should be discontinued immediately. As with other antibiotics, administration of chloramphenicol may result in overgrowth of nonsusceptible organisms, including fungi.
If superinfection occurs, appropriate therapy should be instituted. Chloramphenicol should be used with caution in patients with impaired renal and/or hepatic function and in neonates and infants with immature metabolic processes. Plasma chloramphenicol concentrations should be monitored closely in these patients and dosage should be proportionately reduced. Chloramphenicol is contraindicated in patients with a history of hypersensitivity and/or toxic reactions to the drug.
Pregnancy and Lactation
Safe use of chloramphenicol during pregnancy has not been established. Since the drug crosses the placenta and is distributed into milk, chloramphenicol should be used with extreme caution in pregnant women at term or during labor and in nursing women because of potential toxic effects (e.g., Gray Syndrome) on the fetus or child. (See Cautions: Gray Syndrome.)
Drug Interactions
Effects on Hepatic Clearance of Drugs
Chloramphenicol may interfere with the biotransformation of chlorpropamide, dicumarol, phenytoin, and tolbutamide by inhibiting the activity of microsomal enzymes. The possibility of prolonged plasma half-lives and potentiation of the effects of these and other drugs which are metabolized in the liver should be considered in patients receiving chloramphenicol, and the dosages of these drugs should be adjusted accordingly. In addition, chloramphenicol may prolong the prothrombin time in patients receiving anticoagulant therapy by interfering with vitamin K production by intestinal bacteria.
Phenobarbital
Concurrent administration of chloramphenicol and phenobarbital may result in decreased plasma concentrations of the antibiotic; therefore blood chloramphenicol concentrations should be monitored in patients receiving both drugs.
Antianemia Drugs
When administered concurrently with iron preparations, vitamin B12, or folic acid, chloramphenicol may delay the response to these drugs. Therefore, chloramphenicol therapy should be avoided, if possible, in patients with anemia receiving iron preparations, vitamin B12, or folic acid.
Anti-infective Agents
Chloramphenicol has been reported to antagonize the bactericidal activity of penicillins and aminoglycosides in vitro, and some clinicians recommend that these antibiotics not be used concomitantly. However, in vivo antagonism has not been demonstrated and chloramphenicol has been used successfully with ampicillin or penicillin G or aminoglycosides with no apparent decrease in activity.
Although some in vitro studies showed additive or synergistic antibacterial activity with chloramphenicol and a cephalosporin, there is more recent in vitro evidence of antagonism between cephalosporins (e.g., cefoperazone, cefotaxime, ceftazidime, ceftriaxone) and chloramphenicol against a variety of gram-negative and -positive bacteria, particularly when chloramphenicol was added to the medium before the b-lactam. In addition, at least one case of in vivo antagonism has been reported in an infant with Salmonella enteritidis meningitis.
Therefore, it is recommended that combined therapy with chloramphenicol and a cephalosporin be avoided, particularly when bactericidal activity is considered important. Results of an in vitro study using Klebsiella pneumoniae indicate that chloramphenicol can antagonize the bactericidal activity of aztreonam. 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. Because rifampin induces hepatic microsomal enzymes responsible for the metabolism of chloramphenicol, it has been suggested that concurrent administration of the drugs may result in decreased plasma concentrations of chloramphenicol.
Myelosuppressive Agents
Concomitant administration of chloramphenicol with other drugs that may cause bone marrow depression should be avoided. Mechanism of Action Chloramphenicol usually is bacteriostatic in action, but may be bactericidal in high concentrations or against highly susceptible organisms. Chloramphenicol sodium succinate is inactive until hydrolyzed to free chloramphenicol. This hydrolysis occurs rapidly in vivo.
Chloramphenicol appears to inhibit protein synthesis in susceptible organisms by binding to 50S ribosomal subunits; the primary effect is inhibition of peptide bond formation. The site of action appears to be the same as that of erythromycin, clindamycin, lincomycin, oleandomycin, and troleandomycin. Chloramphenicol also appears to inhibit protein synthesis in rapidly proliferating mammalian cells; reversible bone marrow depression due to chloramphenicol may be the result of inhibition of protein synthesis in mitochondria of bone marrow cells.
Chloramphenicol has been shown to possess immunosuppressive activity when the drug is administered systemically prior to an antigenic stimulus; however, antibody response may not be significantly affected when the drug is administered following the antigen.
Spectrum Chloramphenicol is active in vitro against many gram-positive aerobic bacteria, including Streptococcus pneumoniae and other streptococci, and many gram-negative aerobic bacteria, including Haemophilus influenzae, Neisseria meningitidis, Salmonella, Proteus mirabilis, Pseudomonas mallei, Ps. cepacia, Vibrio cholerae, Francisella tularensis, Yersinia pestis, Brucella, and Shigella. Chloramphenicol is active in vitro against some strains of enterococci resistant to vancomycin; however, experience with chloramphenicol is limited and clinical results have been variable. Chloramphenicol has in vitro activity against Bacillus anthracis.
Anti-infectives are active against the germinated form of B. anthracis, but are not active against the organism while it is still in the spore form. Results of in vitro susceptibility testing of 11 Bacillus 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. Based on interpretive criteria established for staphylococci, these strains are considered susceptible to chloramphenicol. Limited or no clinical data are available to date regarding in vivo activity of chloramphenicol against B. anthracis or use of the drug in the treatment of inhalational anthrax.
Chloramphenicol has in vitro activity against Yersinia pestis. In a study evaluating in vitro susceptibility of 100 Y. pestis isolates obtained from plague patients in Africa, all isolates were inhibited by chloramphenicol concentrations of 0.06-2.0 mcg/mL.; in another study, isolates obtained from plague patients, rats, or fleas from Vietnam were inhibited by chloramphenicol concentrations of 0.5-4 mcg/mL.
Chloramphenicol is active in vitro against many anaerobic bacteria, including Bacteroides fragilis, Clostridium, Fusobacterium, Prevotella melaninogenica (formerly B. melaninogenicus), and Veillonella. Rickettsia, Chlamydia, and Mycoplasma also are inhibited by the drug. Chloramphenicol is inactive against fungi. In general, susceptible bacteria are inhibited in vitro by chloramphenicol concentrations of 0.1-20 mcg/mL; concentrations of 0.1-5 mcg/mL inhibit most susceptible strains of Salmonella, H. influenzae, S. pneumoniae, and Neisseria. Susceptible anaerobic bacteria generally are inhibited in vitro by chloramphenicol concentrations of 8 mcg/mL.
In Vitro Susceptibility Testing
The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to chloramphenicol, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to chloramphenicol, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible. Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a high dosage of the drug can be used.
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. If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to chloramphenicol, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies.
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. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus, Enterococcus, Enterobacteriaceae, Pseudomonas aeruginosa, or Acinetobacter 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. When the disk-diffusion procedure is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM).
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. When testing susceptibility of S. pneumoniae according to NCCLS standardized procedures using Mueller-Hinton agar (supplemented with 5% sheep blood), 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. 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.
Dilution Susceptibility Tests
When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus, Enterococcus, Enterobacteriaceae, and Ps. aeruginosa and other non-Enterobacteriaceae gram-negative bacilli (e.g., other Pseudomonas spp., Acinetobacter, Stenotrophomonas maltophilia) 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.
When broth dilution susceptibility testing is performed according to NCCLS standardized procedures using HTM, Haemophilus 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. When testing susceptibility of S. pneumoniae according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (with 2-5% lysed horse blood), 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. 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.
Resistance
Natural and acquired resistance to chloramphenicol have been demonstrated in vitro and in vivo in strains of staphylococci, Salmonella, Shigella, and Escherichia coli. Chloramphenicol-resistant strains of H. influenzae,
Streptococcus pneumoniae, or Neisseria meningitidis have been reported rarely. In vitro, resistance to chloramphenicol has been shown to be induced in a stepwise manner. Chloramphenicol resistance is caused in part by a plasmid-mediated resistance factor which is acquired by conjugation and enables the resistant bacteria to modify chloramphenicol by acetylation. Resistance to several other anti-infectives (e.g., aminoglycosides, sulfonamides, tetracycline) may also be transferred on the same plasmid. Strains of N. meningitidis resistant to chloramphenicol have been reported in some areas of the world (e.g., Vietnam, France).
Results of an in vitro study evaluating chloramphenicol-resistant clinical isolates of N. meningitidis (all serogroup B) indicate that resistance in these strains was due to production of a chloramphenicol acetyltransferase (CAT) that inactivates the drug; the chloramphenicol-resistant strains also were resistant to streptomycin and sulfonamides, but susceptible to penicillins, cephalosporins, tetracyclines, macrolides, rifampin, and quinolones.
Pharmacokinetics
Absorption
Following IV administration of chloramphenicol sodium succinate, there is considerable interindividual variation in plasma chloramphenicol concentrations attained in adults, children, or neonates.
Chloramphenicol sodium succinate is hydrolyzed in vivo to active chloramphenicol, presumably by esterases in the liver, kidneys, and lungs. The rate and extent of hydrolysis of the ester are highly variable.
Bioavailability of chloramphenicol following IV administration of chloramphenicol sodium succinate also depends on renal clearance of the ester, which also is highly variable. In one study, following IV administration of a single 1-g dose of chloramphenicol sodium succinate to healthy adults, plasma chloramphenicol concentrations ranged from 4.9-12 mcg/mL at 1 hour and 0-5. mcg/mL at 4 hours.
Distribution
Chloramphenicol is widely distributed into most body tissues and fluids including saliva, ascitic fluid, pleural fluid, synovial fluid, and aqueous and vitreous humor. Highest concentrations of the drug are found in the liver and kidneys.
The concentration of chloramphenicol in CSF is reported to be 21-50% of concurrent plasma concentrations in patients with uninflamed meninges and 45-89% of concurrent plasma concentrations in patients with inflamed meninges.
Chloramphenicol readily crosses the placenta, and fetal plasma concentrations of the drug may be 30-80% of concurrent maternal plasma concentrations. Chloramphenicol is distributed into milk.
Chloramphenicol is approximately 60% bound to plasma proteins.
Elimination
The plasma half-life of chloramphenicol in adults with normal renal and hepatic function is 1.5-4. hours. Because premature and newborn infants have immature mechanisms for glucuronide conjugation and renal excretion, usual doses of chloramphenicol that are satisfactory in older infants produce high and prolonged plasma concentrations of the drug in neonates.
The plasma half-life is 24 hours or longer in infants 1-2 days of age and approximately 10 hours in infants 10-16 days of age. The plasma half-life of chloramphenicol is prolonged in patients with markedly reduced hepatic function. In patients with impaired renal function, the plasma half-life of chloramphenicol is not significantly prolonged, although half-lives of the inactive conjugated derivatives may be prolonged.
Plasma chloramphenicol concentrations may be increased in patients with renal impairment following IV administration of chloramphenicol sodium succinate since renal excretion of the succinate ester is reduced in these patients. Chloramphenicol is inactivated primarily in the liver by glucuronyl transferase. In adults with normal renal and hepatic function, approximately 68-99% of a single oral dose of chloramphenicol is excreted in urine over 3 days; 5-15% of the dose is excreted unchanged in urine by glomerular filtration and the rest is excreted by tubular secretion as inactive metabolites, primarily the glucuronide.
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; however, the fraction of the dose excreted unchanged in urine varies considerably, and may range from 6-80% in neonates and children. Probenecid has no effect on chloramphenicol excretion.
Small amounts of unchanged chloramphenicol are excreted in bile and feces following oral administration of the drug. Plasma concentrations of chloramphenicol are not affected by peritoneal dialysis and only small amounts of the drug are removed by hemodialysis. The drug appears to be readily removed by charcoal hemoperfusion.
Chemistry and Stability
Chemistry
Chloramphenicol, an antibiotic originally isolated from Streptomyces venezuelae, is now produced synthetically. 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 pKa 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 contains approximately 2.3 mEq of sodium per g of chloramphenicol.
Stability
Chloramphenicol sodium succinate sterile powder for injection should be stored at 15-25°C. Following reconstitution with sterile water for injection, chloramphenicol sodium succinate injection containing 100 mg of chloramphenicol per mL has a pH of 6.4-7.0 and is stable for 30 days at room temperature. Cloudy solutions of chloramphenicol succinate should not be used.
Chloramphenicol has been reported to be physically incompatible with many 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.
Preparations
Chloramphenicol Sodium Succinate Parenteral For injection 1 g (of chloramphenicol) Chloramphenicol Sodium Succinate Sterile, American Pharmaceutical Partners Chloromycetin® Sodium Succinate, Monarch
| Dosage forms of Chloramphenicol: | ||
|---|---|---|
| Chloramphenicol crystals | Chloramphenicol palm powder | Chloramphen na succ 1 gm vial |
Synonyms of Chloramphenicol:
CAF, CAM, CAP, Chloramfenikol, Chloramphenicole, Chloroamphenicol, Cloroamfenicolo, CPh, D-Chloramphenicol
How can i get Chloramphenicol online over the counter?
You can buy Chloramphenicol OTC in online drugstore with low cost.
Therapeutic classes of Chloramphenicol:
Anti-Bacterial Agents, Protein Synthesis Inhibitors
Delivery
Australia, Canada, Mexico, New Zealand, USA, Europe [Belgium, France, Norway, Holland, Ireland, Spain, Switzerland, Great Britain (UK), Italy] and etc.