CHLORAMPHENICOL, CHLORAMPHENICOL PALMITATE, CHLORAMPHENICOL SODIUM SUCCINATE
Chemistry - Originally isolated from Streptomyces venezuelae, chloramphenicol is now producedsynthetically. It occurs as fine, white to grayish, yellow white, elongated plates or needle-likecrystals with a pKa of 5.5. It is freely soluble in alcohol and about 2.5 mg are soluble in 1 ml ofwater at 25°C.
Chloramphenicol palmitate occurs as a bland mild tasting, fine, white, unctuous, crystalline powderhaving a faint odor. It is insoluble in water and sparingly soluble in alcohol.
Chloramphenicol sodium succinate occurs as a white to light yellow powder. It is freely soluble inboth water or alcohol. Commercially available chloramphenicol sodium succinate for injectioncontains 2.3 mEq of sodium per gram of chloramphenicol.
The sodium succinate powder for injection should be stored at temperatures less than 40°, andpreferably between 15-30°C. After reconstituting the sodium succinate injection with sterile water, the solution is stable for 30 days at room temperature and 6 months if frozen. The solution shouldbe discarded if it becomes cloudy.
The following drugs and solutions are reportedly compatible with chloramphenicol sodiumsuccinate injection: all commonly used intravenous fluids, amikacin sulfate, aminophylline, ampicillin sodium (in syringe for 1 hr.) ascorbic acid, calcium chloride/gluconate, cephalothinsodium, cephapirin sodium, colistimethate sodium, corticotropin, cyanocobalamin, dimenhydrinate, dopamine HCl, ephedrine sulfate, heparin sodium, hydrocortisone sodium succinate, hydroxyzine
HCl, kanamycin sulfate, lidocaine HCl, magnesium sulfate, metaraminol bitartrate, methicillinsodium, methyldopate HCl, methylprednisolone sodium succinate, metronidazole w/ or w/o sodiumbicarbonate, nafcillin sodium, oxacillin sodium, oxytocin, penicillin G potassium/sodium, pentobarbital sodium, phenylephrine HCl w/ or w/o sodium bicarbonate, phytonadione, plasmaprotein fraction, potassium chloride, promazine HCl, ranitidine HCl, sodium bicarbonate, thiopentalsodium, verapamil HCl, and vitamin B-complex with C.
The following drugs and solutions are reportedly incompatible (or compatibility data conflicts)with chloramphenicol sodium succinate injection: chlorpromazine HCl, glycopyrrolate, metoclopramide HCl, oxytetracycline HCl, polymyxin B sulfate, prochlorperazine edislyate/mesylate, promethazine HCl, tetracycline HCl, and vancomycin HCl.
Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.
It is suggested to consult specialized references for more specific information (e.g., Handbook on
Injectable Drugs by Trissel; see bibliography).
Chloramphenicol has a wide spectrum of activity against many gram positive and negative organisms. Gram positive aerobic organisms that are generally susceptible to chloramphenicol includemany streptococci and staphylococci. It is also effective against some gram negative aerobesincluding Neissiera, Brucella, Salmonella, Shigella, and Haemophilus. Many anaerobic bacteria aresensitive to chloramphenicol, including Clostridum, Bacteroides (including B. fragilis),
Fusobacterium, and Veillonella. Chloramphenicol also has activity against Nocardia, Chlamydia,
Mycoplasma, and Rickettsia.
Chloramphenicol is widely distributed throughout the body. Highest levels are found in the liverand kidney, but the drug attains therapeutic levels in most tissues and fluids, including the aqueousand vitreous humor, and synovial fluid. CSF concentrations may be up tp 50% of those in theserum when meninges are uninflamed and higher when meninges are inflamed. A 4-6 hour lag timebefore CSF peak levels to occur may be seen. Chloramphenicol concentrations in the prostate areapproximately 50% of those in the serum. Because only a small amount of the drug is excretedunchanged into the urine in dogs, chloramphenicol may not be the best choice for lower urinarytract infections in that species. The volume of distribution of chloramphenicol has been reported as1.8 L/kg in the dog, 2.4 L/kg in the cat, and 1.41 L/kg in horses. Chloramphenicol is about 30-60%bound to plasma proteins, enters milk and crosses the placenta.
In most species, chloramphenicol is eliminated primarily by hepatic metabolism via glucuronidative mechanisms. Only about 5-15% of the drug is excreted unchanged in the urine. Thecat, having little ability to glucuronidate drugs, excretes 25% or more of a dose as unchanged drugin the urine.
The elimination half-life has been reported as 1.1-5 hours in dogs, <1 hour in foals & ponies, and4-8 hours in cats. The elimination half-life of chloramphenicol in birds is highly species variable, ranging from 26 minutes in pigeons to nearly 5 hours in bald eagles and peafowl.
The usual serum therapeutic range for chloramphenicol is 5-15 micrograms/ml.
Chloramphenicol should be used with caution in neonatal animals, particularly in young kittens. Inneonates (humans), circulatory collapse (so-called "Gray-baby syndrome") has occurred withchloramphenicol, probably due to toxic levels accumulating secondary to an inability to conjugatethe drug or excrete the conjugate effectively. Because chloramphenicol is found in milk at 50% ofserum levels (in humans), the drug should be given with caution to nursing bitches or queens, particularly within the first week after giving birth.
One manufacturer (Osborn) states that chloramphenicol "should not be administered to dogsmaintained for breeding purposes". Chloramphenicol has not been determined to be safe for useduring pregnancy. The drug may decrease protein synthesis in the fetus, particularly in the bonemarrow. It should only be used when the benefits of therapy clearly outweigh the risks..
Other effects that may be noted include, anorexia, vomiting, diarrhea and depression.
It has been said that cats tend to be more sensitive to developing adverse reactions to chloramphenicol than dogs, but this is probably more as a result of the drug's longer half-life in the cat. Itis true that cats dosed at 50 mg/kg q12h for 2-3 weeks do develop a high incidence of adverse effects and should be closely monitored when prolonged high-dose therapy is necessary.
For more information on the toxicity of chloramphenicol, refer to the Adverse Effects section above.
Chloramphenicol has been demonstrated to prolong the duration of pentobarbital anesthesia by120% in dogs, and 260% in cats. Phenobarbital may also decrease the plasma concentrations ofchloramphenicol. In dogs receiving both chloramphenicol and primidone, anorexia and CNS depression may occur. Serum monitoring of the affected drugs should be considered if any of these drugs are to be used concurrently with chloramphenicol.
The hematologic response to iron salts and Vitamin B12 can be decreased when concomitantlyadministered with chloramphenicol. Chloramphenicol should be used with extreme caution, if at all, with other drugs that can cause myelosuppression (e.g., cyclophosphamide).
Penicillin may slightly increase the serum half-life of chloramphenicol. Chloramphenicol mayantagonize the bactericidal activity of the penicillins or aminoglycosides. This antagonism hasnot been demonstrated in vivo, and these drug combinations have been used successfully manytimes clinically. Rifampin may decrease serum chloramphenicol levels. Other antibiotics that bindto the 50S ribosomal subunit of susceptible bacteria (erythromycin, clindamycin, lincomycin, tylosin, etc.) may potentially antagonize the activity of chloramphenicol or vice versa, but theclinical significance of this potential interaction has not been determined.
Chloramphenicol may suppress antibody production if given prior to an antigenic stimulus and may affect responses to vaccinations. If administered after the antigen challenge, immune response may not be altered. Immunizations should be postponed, if possible, in animals receiving chloramphenicol.
Drug/Laboratory Interactions - False-positive glucosuria has been reported, but the incidence is unknown.
Chloramphenicol palmitate occurs as a bland mild tasting, fine, white, unctuous, crystalline powderhaving a faint odor. It is insoluble in water and sparingly soluble in alcohol.
Chloramphenicol sodium succinate occurs as a white to light yellow powder. It is freely soluble inboth water or alcohol. Commercially available chloramphenicol sodium succinate for injectioncontains 2.3 mEq of sodium per gram of chloramphenicol.
Storage, Stability, Compatibility
Chloramphenicol capsules and tablets should be stored intight containers at room temperature (15-30°C). The palmitate oral suspension should be stored intight containers at room temperature and protected from light or freezing.The sodium succinate powder for injection should be stored at temperatures less than 40°, andpreferably between 15-30°C. After reconstituting the sodium succinate injection with sterile water, the solution is stable for 30 days at room temperature and 6 months if frozen. The solution shouldbe discarded if it becomes cloudy.
The following drugs and solutions are reportedly compatible with chloramphenicol sodiumsuccinate injection: all commonly used intravenous fluids, amikacin sulfate, aminophylline, ampicillin sodium (in syringe for 1 hr.) ascorbic acid, calcium chloride/gluconate, cephalothinsodium, cephapirin sodium, colistimethate sodium, corticotropin, cyanocobalamin, dimenhydrinate, dopamine HCl, ephedrine sulfate, heparin sodium, hydrocortisone sodium succinate, hydroxyzine
HCl, kanamycin sulfate, lidocaine HCl, magnesium sulfate, metaraminol bitartrate, methicillinsodium, methyldopate HCl, methylprednisolone sodium succinate, metronidazole w/ or w/o sodiumbicarbonate, nafcillin sodium, oxacillin sodium, oxytocin, penicillin G potassium/sodium, pentobarbital sodium, phenylephrine HCl w/ or w/o sodium bicarbonate, phytonadione, plasmaprotein fraction, potassium chloride, promazine HCl, ranitidine HCl, sodium bicarbonate, thiopentalsodium, verapamil HCl, and vitamin B-complex with C.
The following drugs and solutions are reportedly incompatible (or compatibility data conflicts)with chloramphenicol sodium succinate injection: chlorpromazine HCl, glycopyrrolate, metoclopramide HCl, oxytetracycline HCl, polymyxin B sulfate, prochlorperazine edislyate/mesylate, promethazine HCl, tetracycline HCl, and vancomycin HCl.
Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.
It is suggested to consult specialized references for more specific information (e.g., Handbook on
Injectable Drugs by Trissel; see bibliography).
Pharmacology - CHLORAMPHENICOL, CHLORAMPHENICOL PALMITATE, CHLORAMPHENICOL SODIUM SUCCINATE
Chloramphenicol usually acts as a bacteriostatic antibiotic, but at higher concentrations or against some very susceptible organisms it can be bactericidal. Chloramphenicol acts by binding to the 50S ribosomal subunit of susceptible bacteria, thereby preventing bacterial proteinsynthesis. Erythromycin, clindamycin, lincomycin, tylosin, etc., also bind to the same site, but unlike them, chloramphenicol appears to also have an affinity for mitochondrial ribosomes of rapidly proliferating mammalian cells (e.g., bone marrow) which may result in a reversible bone marrowsuppression.Chloramphenicol has a wide spectrum of activity against many gram positive and negative organisms. Gram positive aerobic organisms that are generally susceptible to chloramphenicol includemany streptococci and staphylococci. It is also effective against some gram negative aerobesincluding Neissiera, Brucella, Salmonella, Shigella, and Haemophilus. Many anaerobic bacteria aresensitive to chloramphenicol, including Clostridum, Bacteroides (including B. fragilis),
Fusobacterium, and Veillonella. Chloramphenicol also has activity against Nocardia, Chlamydia,
Mycoplasma, and Rickettsia.
Uses, Indications
Chloramphenicol is used for a variety of infections in small animals andhorses, particularly those caused by anaerobic bacteria. Because of the human public health implications, the use of chloramphenicol in animals used for food production is banned by the FDA.Pharmacokinetics - CHLORAMPHENICOL, CHLORAMPHENICOL PALMITATE, CHLORAMPHENICOL SODIUM SUCCINATE
Chloramphenicol is rapidly absorbed after oral administration with peakserum levels occurring approximately 30 minutes after dosing. The palmitate oral suspensionproduces significantly lower peak serum levels when administered to fasted cats. The sodiumsuccinate salt is rapidly and well absorbed after IM or SQ administration in animals and, contrary tosome recommendations, need not be administered only intravenously. The palmitate and sodiumsuccinate is hydrolyzed in the GI tract and liver to the base.Chloramphenicol is widely distributed throughout the body. Highest levels are found in the liverand kidney, but the drug attains therapeutic levels in most tissues and fluids, including the aqueousand vitreous humor, and synovial fluid. CSF concentrations may be up tp 50% of those in theserum when meninges are uninflamed and higher when meninges are inflamed. A 4-6 hour lag timebefore CSF peak levels to occur may be seen. Chloramphenicol concentrations in the prostate areapproximately 50% of those in the serum. Because only a small amount of the drug is excretedunchanged into the urine in dogs, chloramphenicol may not be the best choice for lower urinarytract infections in that species. The volume of distribution of chloramphenicol has been reported as1.8 L/kg in the dog, 2.4 L/kg in the cat, and 1.41 L/kg in horses. Chloramphenicol is about 30-60%bound to plasma proteins, enters milk and crosses the placenta.
In most species, chloramphenicol is eliminated primarily by hepatic metabolism via glucuronidative mechanisms. Only about 5-15% of the drug is excreted unchanged in the urine. Thecat, having little ability to glucuronidate drugs, excretes 25% or more of a dose as unchanged drugin the urine.
The elimination half-life has been reported as 1.1-5 hours in dogs, <1 hour in foals & ponies, and4-8 hours in cats. The elimination half-life of chloramphenicol in birds is highly species variable, ranging from 26 minutes in pigeons to nearly 5 hours in bald eagles and peafowl.
The usual serum therapeutic range for chloramphenicol is 5-15 micrograms/ml.
Contraindications, Precautions, Reproductive Safety
Chloramphenicol is contraindicated inpatients hypersensitive to it. Because of the potential for hematopoietic toxicity, the drug should beused with extreme caution, if at all, in patients with preexisting hematologic abnormalities, especiallya preexisting non-regenerative anemia. The drug should only be used in patients in hepatic failurewhen no other effective antibiotics are available. Chloramphenicol should be used with caution inpatients with impaired hepatic or renal function as drug accumulation may occur. Those patientsmay need dosing adjustment, and monitoring of blood levels should also be considered in thesepatients.Chloramphenicol should be used with caution in neonatal animals, particularly in young kittens. Inneonates (humans), circulatory collapse (so-called "Gray-baby syndrome") has occurred withchloramphenicol, probably due to toxic levels accumulating secondary to an inability to conjugatethe drug or excrete the conjugate effectively. Because chloramphenicol is found in milk at 50% ofserum levels (in humans), the drug should be given with caution to nursing bitches or queens, particularly within the first week after giving birth.
One manufacturer (Osborn) states that chloramphenicol "should not be administered to dogsmaintained for breeding purposes". Chloramphenicol has not been determined to be safe for useduring pregnancy. The drug may decrease protein synthesis in the fetus, particularly in the bonemarrow. It should only be used when the benefits of therapy clearly outweigh the risks..
Adverse Effects, Warnings
While the toxicity of chloramphenicol in humans has been muchdiscussed, the drug is considered by most to have a low order of toxicity in adult companionanimals when appropriately dosed. The development of aplastic anemia reported in humans, does not appear to be a significantproblem for veterinary patients. However, a dose-related bone marrow suppression (reversible) isseen in all species, primarily with long-term therapy. Early signs of bone marrow toxicity can include vacuolation of the many of the early cells of the myeloid and erythroid series, lymphocytopenia, and neutropenia.Other effects that may be noted include, anorexia, vomiting, diarrhea and depression.
It has been said that cats tend to be more sensitive to developing adverse reactions to chloramphenicol than dogs, but this is probably more as a result of the drug's longer half-life in the cat. Itis true that cats dosed at 50 mg/kg q12h for 2-3 weeks do develop a high incidence of adverse effects and should be closely monitored when prolonged high-dose therapy is necessary.
Overdosage, Acute Toxicity
Because of the potential for serious bone marrow toxicity, largeoverdoses of chloramphenicol should be handled by emptying the gut using standard protocols.For more information on the toxicity of chloramphenicol, refer to the Adverse Effects section above.
Drug Interactions
Chloramphenicol can inhibit the hepatic metabolism of several drugs, including phenytoin, primidone, phenobarbital, pentobarbital, and cyclophosphamide.Chloramphenicol has been demonstrated to prolong the duration of pentobarbital anesthesia by120% in dogs, and 260% in cats. Phenobarbital may also decrease the plasma concentrations ofchloramphenicol. In dogs receiving both chloramphenicol and primidone, anorexia and CNS depression may occur. Serum monitoring of the affected drugs should be considered if any of these drugs are to be used concurrently with chloramphenicol.
The hematologic response to iron salts and Vitamin B12 can be decreased when concomitantlyadministered with chloramphenicol. Chloramphenicol should be used with extreme caution, if at all, with other drugs that can cause myelosuppression (e.g., cyclophosphamide).
Penicillin may slightly increase the serum half-life of chloramphenicol. Chloramphenicol mayantagonize the bactericidal activity of the penicillins or aminoglycosides. This antagonism hasnot been demonstrated in vivo, and these drug combinations have been used successfully manytimes clinically. Rifampin may decrease serum chloramphenicol levels. Other antibiotics that bindto the 50S ribosomal subunit of susceptible bacteria (erythromycin, clindamycin, lincomycin, tylosin, etc.) may potentially antagonize the activity of chloramphenicol or vice versa, but theclinical significance of this potential interaction has not been determined.
Chloramphenicol may suppress antibody production if given prior to an antigenic stimulus and may affect responses to vaccinations. If administered after the antigen challenge, immune response may not be altered. Immunizations should be postponed, if possible, in animals receiving chloramphenicol.
Drug/Laboratory Interactions - False-positive glucosuria has been reported, but the incidence is unknown.