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Chloramphenicol

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Chemistry - Originally isolated from Streptomyces venezuelae, chloramphenicol is now produced synthetically. It occurs as fine, white to grayish, yellow white, elongated plates or needle-like crystals with a pKa of 5.5. It is freely soluble in alcohol and about 2.5 mg are soluble in 1 ml of water at 25°C.

 

Chloramphenicol palmitate occurs as a bland mild tasting, fine, white, unctuous, crystalline powder having 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 in both water or alcohol. Commercially available chloramphenicol sodium succinate for injection contains 2.3 mEq of sodium per gram of chloramphenicol.

 

Storage/Stability/Compatibility - Chloramphenicol capsules and tablets should be stored in tight containers at room temperature (15-30°C). The palmitate oral suspension should be stored in tight containers at room temperature and protected from light or freezing.

 

The sodium succinate powder for injection should be stored at temperatures less than 40°, and preferably 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 should be discarded if it becomes cloudy.

 

The following drugs and solutions are reportedly compatible with chloramphenicol sodium succinate injection: all commonly used intravenous fluids, amikacin sulfate, aminophylline, ampicillin sodium (in syringe for 1 hr.) ascorbic acid, calcium chloride/gluconate, cephalothin sodium, cephapirin sodium, colistimethate sodium, corticotropin, cyanocobalamin, dimenhydrinate, dopamine HCl, ephedrine sulfate, heparin sodium, hydrocortisone sodium succinate, hyoxyzine HCl, kanamycin sulfate, lidocaine HCl, magnesium sulfate, metaraminol bitartrate, methicillin sodium, methyldopate HCl, methylprednisolone sodium succinate, metronidazole w/ or w/o sodium bicarbonate, nafcillin sodium, oxacillin sodium, oxytocin, penicillin G potas­sium/sodium, pentobarbital sodium, phenylephrine HCl w/ or w/o sodium bicarbonate, phytonadione, plasma protein fraction, potassium chloride, promazine HCl, ranitidine HCl, sodium bi­carbonate, thiopental sodium, 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 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 protein synthesis. 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 marrow suppression.

 

Chloramphenicol has a wide spectrum of activity against many gram positive and negative or­ganisms. Gram positive aerobic organisms that are generally susceptible to chloramphenicol include many streptococci and staphylococci. It is also effective against some gram negative aerobes including Neissiera, Brucella, Salmonella, Shigella, and Haemophilus. Many anaerobic bacteria are sensitive 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 and horses, 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 is rapidly absorbed after oral administration with peak serum levels occurring approximately 30 minutes after dosing. The palmitate oral suspension produces significantly lower peak serum levels when administered to fasted cats. The sodium succinate salt is rapidly and well absorbed after IM or SQ administration in animals and, contrary to some recommendations, need not be administered only intravenously. The palmitate and sodium succinate is hydrolyzed in the GI tract and liver to the base.

 

Chloramphenicol is widely distributed throughout the body. Highest levels are found in the liver and kidney, but the drug attains therapeutic levels in most tissues and fluids, including the aqueous and vitreous humor, and synovial fluid. CSF concentrations may be up tp 50% of those in the serum when meninges are uninflamed and higher when meninges are inflamed. A 4-6 hour lag time before CSF peak levels to occur may be seen. Chloramphenicol concentrations in the prostate are approximately 50% of those in the serum. Because only a small amount of the drug is excreted unchanged into the urine in dogs, chloramphenicol may not be the best choice for lower urinary tract infections in that species. The volume of distribution of chloramphenicol has been reported as 1.8 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. The cat, having little ability to glucuronidate drugs, excretes 25% or more of a dose as unchanged drug in the urine.

 

The elimination half-life has been reported as 1.1-5 hours in dogs, <1 hour in foals & ponies, and 4-8 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 in patients hypersensitive to it. Because of the potential for hematopoietic toxicity, the drug should be used with extreme caution, if at all, in patients with preexisting hematologic abnormalities, especially a preexisting non-regenerative anemia. The drug should only be used in patients in hepatic failure when no other effective antibiotics are available. Chloramphenicol should be used with caution in patients with impaired hepatic or renal function as drug accumulation may occur. Those patients may need dosing adjustment, and monitoring of blood levels should also be con­sidered in these patients.

 

Chloramphenicol should be used with caution in neonatal animals, particularly in young kittens. In neonates (humans), circulatory collapse (so-called “Gray-baby syndrome”) has occurred with chloramphenicol, probably due to toxic levels accumulating secondary to an inability to conjugate the drug or excrete the conjugate effectively. Because chloramphenicol is found in milk at 50% of serum 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 dogs maintained for breeding purposes”. Chloramphenicol has not been determined to be safe for use during pregnancy. The drug may decrease protein synthesis in the fetus, particularly in the bone marrow. 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 much discussed, the drug is considered by most to have a low order of toxicity in adult companion animals when appropriately dosed.

 

The development of aplastic anemia reported in humans, does not appear to be a significant problem for veterinary patients. However, a dose-related bone marrow suppression (reversible) is seen 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. It is 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, large overdoses 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 by 120% in dogs, and 260% in cats. Phenobarbital may also decrease the plasma concentrations of chloramphenicol. 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 concomitantly administered 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 may antagonize the bactericidal activity of the penicillins or aminoglycosides. This antagonism has not been demonstrated in vivo, and these drug combinations have been used successfully many times clinically. Rifampin may decrease serum chloramphenicol levels. Other antibiotics that bind to the 50S ribosomal subunit of susceptible bacteria (erythromycin, clindamycin, lin­comycin, tylosin, etc.) may potentially antagonize the activity of chloramphenicol or vice versa, but the clinical 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.

 

Doses -

Horses:

For susceptible infections:

a)   10 - 50 mg/kg PO qid. If using palmitate salt, give 20 - 50 mg/kg PO qid. For sodium succinate: 20 - 50 mg/kg IM or IV qid. (Robinson 1987)

b)   Chloramphenicol sodium succinate: 25 mg/kg IM q8h (Baggot and Prescott 1987)

c)   Foals: Chloramphenicol sodium succinate: 50 mg/kg IV q6-8h (use longer dosage interval in premature foals and those less than 2 days old). (Caprile and Short 1987)

d)   45 - 60 mg/kg PO q8h; 45 - 60 mg/kg IM, SQ or IV q6-8h (USPC 1990)

 

 

Monitoring Parameters -

1)   Clinical efficacy

2)   Adverse effects; chronic therapy should be associated with routine CBC monitoring

 

 

Client Information - Must not be used in any animal to be used for food production. There is evidence that humans exposed to chloramphenicol have an increased risk of developing a fatal aplastic anemia. Products should be handled with care. Do not inhale powder and wash hands after handling tablets. Crushed tablets or capsule contents are very bitter tasting and animals may not accept the drug if presented in this manner.

 

Dosage Forms/Preparations/FDA Approval Status -

 

Veterinary-Approved Products:

Note: The oral suspension (palmitate salt) has reportedly been discontinued and the availability of any veterinary-labeled oral dosage form has been sporadic at best.

 

Chloramphenicol Oral Tablets 100 mg, 250 mg, 500 mg, 1 gram;  Approved for use in dogs only.

 

Veterinary-labeled chloramphenicol capsules may also be commercially available.

 

Human-Approved Products:

Chloramphenicol Capsules 250 mg; Chloromycetin Kapseals® (Parke-Davis), generic; (Rx)

 

Chloramphenicol Sodium Succinate Powder for Injection 100 mg/ml (as sodium succinate) when reconstituted 1 g vials; Chloromycetin® Sodium Succinate  (Parke-Davis), generic; (Rx)

 

    Topical, otic and ophthalmic preparations are also available.

 

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