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Professional Version

Phenicols Use in Animals


Melissa A. Mercer

, DVM, MS, DACVIM-LA, Virginia Maryland College of Veterinary Medicine

Reviewed/Revised Sep 2022 | Modified Nov 2022
Topic Resources

Chloramphenicol is a highly effective and well-tolerated broad-spectrum antimicrobial. However, because it causes blood dyscrasias, it is prohibited for use in food-producing animals in several countries, including the US and Canada. Chloramphenicol is only approved in dogs in the US, although it is used in an extralabel fashion in horses with some frequency. Thiamphenicol is less effective but safer than chloramphenicol and is not approved for veterinary use in the US. Florfenicol, a thiamphenicol derivative, is much more active in vitro than chloramphenicol against many pathogenic strains of bacteria. Florfenicol is approved for use in cattle, as an oral medicated feed or water in swine and fish, and as a topical otic preparation in dogs.

General Properties

Chloramphenicol is a relatively simple neutral nitrobenzene derivative with a bitter taste. It is highly lipid soluble and is used either as the free base or in ester forms (eg, the neutral-tasting palmitate for administration PO and the water-soluble sodium succinate for parenteral injection). Chloramphenicol is a relatively stable compound and is unaffected by boiling, provided that a pH of 9 is not exceeded. The nitrophenol group of chloramphenicol is replaced by a methyl sulfonyl group for thiamphenicol and florfenicol; florfenicol also contains a fluorine molecule. These structural changes improve efficacy, reduce toxicity, and for florfenicol, the fluorine molecule decreases bacterial resistance.

Antimicrobial Activity

Mode of Action of Phenicols in Animals

The phenicols inhibit microbial protein synthesis by binding to the 50S subunit of the 70S ribosome and impairing peptidyl transferase activity. Because peptide-bond formation is inhibited, peptides cannot elongate. The effect is usually bacteriostatic but, at high concentrations, chloramphenicol may be bactericidal for some species. Protein synthesis is inhibited in both prokaryotic and eukaryotic (mitochondrial) ribosomes.

Bacterial Resistance to Phenicols in Animals

Resistance against chloramphenicol develops slowly and in a stepwise fashion. In clinical bacterial isolates, high-level plasmid-mediated resistance reflects the production of chloramphenicol acetyltransferase (encoded for by the cat gene) and results in acetylation of the molecule, which can no longer bind to the ribosome. Other inactivating enzymes also may be involved. In resistant gram-negative bacteria, chloramphenicol acetyltransferase is a constitutive enzyme; in gram-positive organisms, the enzyme is inducible. The fluorine atom of florfenicol prevents acetylation, thus enhancing the efficacy of this drug.

In Pseudomonas aeruginosa and in strains of Proteus and Klebsiella spp, resistance is also nonenzymatic and is based on an inducible permeability block that is both chromosomal and plasmid-mediated. Decreased permeability contributes to low-level resistance. Very rarely, resistance may reflect altered ribosomal subunit structure and binding. Resistance to chloramphenicol often develops together with resistance to tetracycline, erythromycin, streptomycin, ampicillin, and other antimicrobials because of multiple genes being carried on the same plasmid.

Antimicrobial Spectra of Phenicols in Animals

Many genera of gram-positive and gram-negative bacteria and several anaerobes such as Bacteroides fragilis, as well as Rickettsia and Chlamydia spp, are susceptible to phenicols. Chloramphenicol is notable for its anaerobic spectrum. Of special note is the efficacy against many MRSA and Salmonella, Pasteurella, Mycoplasma, and Brucella spp but the resistance of most strains of P aeruginosa.

Pharmacokinetic Features

Absorption of Phenicols in Animals

Absorption occurs promptly and rapidly from the upper GI tract when chloramphenicol base is administered PO to nonruminant animals. Blood concentrations usually are maximal in 1–3 hours. Because ruminal microflora readily decrease the nitro group, chloramphenicol is inactivated in the ruminoreticulum and is not available for absorption. The larger ester forms of chloramphenicol require hydrolysis via lipases to release the antimicrobial for absorption from the GI tract; thus, the systemic availability of chloramphenicol is delayed when the palmitate and other ester preparations are used.

Generic inequivalence has occurred with oral dosage forms. The presence of food and intestinal protectants does not interfere with absorption of chloramphenicol, although drugs that depress GI motility do. Chloramphenicol bioavailability has been noted to decline after multiple doses in horses. Florfenicol is rapidly absorbed after administration PO, although milk interferes with absorption.

Chloramphenicol sodium succinate may be injected both IV and IM. However, hydrolysis is required in the body because only free chloramphenicol base is active. The kinetics of this hydrolysis reaction may be slow and incomplete, with considerable individual and species variability. The absorption of chloramphenicol base itself from IM injection sites is notably restricted. For example, in horses, the therapeutic blood concentration of 5 mg/mL is achieved at a dose of 50 mg/kg, IM, after only 6–8 hours. Chloramphenicol base is absorbed after IP injection. Florfenicol is available as an injectable solution intended for IM or SC use.

Distribution of Phenicols in Animals

Approximately 40%–60% of chloramphenicol in plasma is reversibly bound to albumin, and the free fraction readily diffuses into almost all tissues (including the brain); highest concentrations are reached in the kidneys, liver, and bile. Substantial concentrations (~50% of plasma concentrations) are also reached in many body fluids such as the CSF and aqueous humor. Milk concentrations are ~50% those of plasma but may be higher in mastitis. Transplacental diffusion occurs in all species, with concentrations of ~75% being reached in the fetus as compared with the dam.

The blood-prostate barrier is an exception to the extensive intracorporeal distribution of chloramphenicol, and concentrations in the inflamed prostate are low to nil. Approximately 15%–20% of peak serum concentrations are present within abscesses. Florfenicol also penetrates most body tissues, although penetration of CSF and aqueous humor is less than that of chloramphenicol. Florfenicol does penetrate the milk of lactating cows and residues persist for an extended duration.

Biotransformation of Phenicols in Animals

Unlike many other antibacterial agents, chloramphenicol undergoes extensive hepatic metabolism. Although some nitroreduction and other phase I reactions occur, free chloramphenicol is biotransformed primarily via glucuronide conjugation. Urinary products after administration of chloramphenicol sodium succinate include inactive forms, mainly the unhydrolyzed sodium succinate and the glucuronide; only 5%–15% appears as biologically active chloramphenicol.

There are several clinical concerns with respect to the biotransformation of chloramphenicol. In cats, a characteristic genetic deficiency in glucuronyl transferase activity leads to plasma half-lives that are often considerably longer than those in other species (eg, cats, 5.1 hours; ponies, 54 minutes), and dosages need to be adjusted accordingly. Phase I metabolism may also be deficient in cats. Very young animals frequently do not have full microsomal enzyme capabilities, and the plasma half-lives of chloramphenicol in the young (< 4 weeks old) of many species are often much longer than those of adults. Foals appear to be a notable exception to this generalization. Liver disease also prevents chloramphenicol from undergoing normal metabolic degradation, and active antimicrobial accumulates in the body.

Excretion of Phenicols in Animals

The principal route of excretion of parent drug (minor) and glucuronide is renal. Free chloramphenicol and the chloramphenicol sodium succinate dosage form undergo glomerular filtration (5%–10%), whereas the glucuronide metabolite is eliminated via tubular secretion (90%–95%). Only 5%–15% of chloramphenicol is present in the urine in the active, unchanged form. The biliary route also plays a part in excretion; however, enterohepatic cycling is often pronounced, and usually only a small amount of chloramphenicol is recoverable in feces. Enterohepatic cycling prolongs blood concentrations to some degree in herbivores.

Pharmacokinetic Values of Phenicols in Animals


The plasma half-life of chloramphenicol varies among species and depends on age in some species. The specific volumes of distribution usually reflect the extensive diffusion into tissues ( see Table: Elimination and Distribution of Chloramphenicol and Florfenicol Elimination and Distribution of Chloramphenicol and Florfenicol Elimination and Distribution of Chloramphenicol and Florfenicol ). Dose rates and frequencies are typically adjusted for the species and age of the animal. Florfenicol is eliminated via the kidneys.

Therapeutic Indications and Dose Rates


Chloramphenicol is used to treat both systemic and local infections. Salmonellosis and Bacteroides sepsis have been specific indications; however, use of chloramphenicol has decreased in the absence of an easily accessible, commercially available, approved preparation. Florfenicol is approved for use in treatment of bovine respiratory disease. Because problematic organisms such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus pseudintermedius (MRSP), and multidrug-resistant enterococci often retain susceptibility, chloramphenicol is regularly used in these cases.

General dosages for chloramphenicol and florfenicol are listed in Dosages of Chloramphenicol and Florfenicol Dosages of Chloramphenicol and Florfenicol Dosages of Chloramphenicol and Florfenicol . The dose rate and frequency should be adjusted as needed for the individual animal.

Special Clinical Concerns

Adverse Effects and Toxicity of Phenicols in Animals

In people, chloramphenicol (but not florfenicol) can produce two distinctive syndromes of bone marrow suppression. One form is characterized by nonregenerative anemia (with or without thrombocytopenia or leukopenia), increased serum iron, bone marrow hypocellularity, cytoplasmic vacuolization of blast cells and lymphocytes, and maturation arrest of erythroid and myeloid precursors. This suppression is dose-dependent and reversible, and is more likely to occur with florfenicol than chloramphenicol. Daily doses of 50 mg/kg for 3 weeks can produce similar effects in cats. Milder hematologic effects are evident in dogs at much higher daily dosages (225 mg/kg). Such blood dyscrasias may also occur in susceptible neonatal animals given standard adult doses of chloramphenicol. This toxic effect is postulated to be due to interference with mRNA and protein synthesis in rapidly multiplying cells.

The second form of bone marrow suppression is an irreversible aplastic anemia that is not related to dose or duration and may appear after the drug has been discontinued. Peripheral blood showing pancytopenia may be associated with hypoplastic or aplastic bone marrow. The incidence is ~1:25,000–40,000. Because tissue residues in production animals might induce aplastic anemia in people, use of chloramphenicol in production animals is prohibited in the US and several other countries. Due to this risk, humans should wear gloves and be properly educated on safe drug handling when administering chloramphenicol to animals. A form of aplastic anemia, apparently a type of hypersensitivity reaction to chloramphenicol, has been recognized in dogs and cats.

Gastrointestinal disturbances can develop in all nonruminant animals treated with chloramphenicol administered PO. Use in neonatal calves leads to a malabsorption syndrome associated with ultrastructural and functional changes of the small-intestinal enterocytes. Anorexia and lethargy have occurred in cats treated for >1 week.

Because chloramphenicol can suppress anamnestic immune responses, animals should not be vaccinated while being treated with this antimicrobial. Because of the ability of chloramphenicol to inhibit protein synthesis, excessive topical application on wounds may delay healing.

In both male and female rats, chloramphenicol has adversely affected the structure and functions of the gonads. In large animals, adverse clinical signs are most often associated with propylene glycol–based preparations that, when infused rapidly IV, may result in collapse, hemolysis, and death.

Notwithstanding the severity of the chloramphenicol-associated adverse effects, chloramphenicol is relatively safe, provided overdosage is avoided, courses of treatment are limited to 1 week, the dose is decreased for newborn animals and for animals with impaired liver function, and there is no evidence of preexisting bone marrow depression.

Interactions With Phenicols in Animals

Chloramphenicol is a potent noncompetitive microsomal enzyme inhibitor that can substantially prolong the duration of action of several drugs administered concurrently. Frank toxic effects are likely if administration is repeated. Examples of such drugs include pentobarbital, codeine, phenobarbital, xylazine, cyclophosphamide, phenytoin, NSAIDs, and coumarins.

In combination with sulfamethoxypyridazine, chloramphenicol can cause hepatic damage. Chloramphenicol also delays the response of anemia to iron, folic acid, and vitamin B12. It interferes with the actions of many bactericidal drugs, such as the penicillins, cephalosporins, and aminoglycosides, and such combinations should not be used under most circumstances. Aqueous solutions of chloramphenicol sodium succinate should not be mixed with other preparations before administration because of a high incidence of incompatibility.

Chloramphenicol should not be administered concurrently with other antibacterial agents that bind to the 50S ribosomal subunit (eg, the macrolides and lincosamides).

Effects of Phenicols on Laboratory Tests in Animals

Chloramphenicol may cause increased alkaline phosphatase activity and prothrombin time. Thrombocyte and WBC counts may be decreased. Anemia becomes evident in extreme cases. False-positive glucosuria test results are possible.

Drug Withdrawal and Milk Discard Times of Phenicols in Animals

The use of chloramphenicol in food-producing animals is prohibited in several countries including the US; in others, withdrawal times vary considerably. Florfenicol should not be used in dairy cattle > 20 months old, veal calves, calves < 1 month old, or calves on an all-milk diet. Although florfenicol is not prohibited from extralabel use in production animals in the US, veterinarians should be aware that the use of florfenicol in an extralabel fashion will result in extremely prolonged withdrawal intervals, particularly for lactating animals.

Regulatory requirements for withdrawal times for production animals and milk discard times vary among countries. These must be followed carefully to prevent food residues and consequent public health implications. Withdrawal times can vary between products, even for the same drug. Therefore, when using products according to label recommendations, it is imperative to follow the label meat and milk withdrawal times for the particular product used.

For instances of extralabel drug use (ELDU), it is recommended to contact a country-specific advisory program to obtain evidence-based withdrawal recommendations extrapolated from known species pharmacokinetics. In the US, veterinarians may contact the Food Animal Residue Avoidance Databank (FARAD, for withdrawal recommendations.

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