Lincosamides are derivatives of an amino acid and a sulfur-containing octose. They are monobasic and more stable in salt forms (hydrochlorides and phosphates). In veterinary medicine, lincomycin and clindamycin are the most frequently used in this class, and pirlimycin is approved as an intramammary infusion in cattle.
Mode of Action of Lincosamides in Animals
Lincomycin and clindamycin bind exclusively to the 50S subunit of bacterial ribosomes and suppress protein synthesis via inhibition of peptidyl transferases. Lincosamides, despite not being structurally related, use the same ribosomal binding sites as macrolides, streptogramins, and phenicols. The lincosamides are bacteriostatic or bactericidal depending on the concentration, bacterial species, and bacterial load. Activity is enhanced at an alkaline pH. Efficacy is considered time dependent.
Bacterial Resistance to Lincosamides in Animals
Lincosamides are generally ineffective against facultative anaerobic (but not anaerobic) gram-negative bacteria. This is because gram-negative bacteria exhibit impermeability and methylation of the ribosomal binding site. Resistance to lincosamides appears slowly, perhaps as a result of chromosomal mutation. Plasmid-mediated resistance has been found in strains of Bacteroides fragilis. Resistance appears to be due to plasmid or chromosomally mediated post-transcriptional methylation of the 50S ribosomal subunit.
Cross-resistance occurs with macrolides and streptogramin group B, due to similarities in their mechanism of action, and is classified as macrolide-lincosamide-streptogramin B, or MLSB, resistance. Cross-resistance may also include ketolides (ie, telithromycin) and is referred to as MLSK resistance. There is potential for a dissociated inducible cross-resistance pattern in MLSB bacteria where macrolide-resistant bacteria that are initially susceptible to lincosamides develop rapid resistance to lincosamides after exposure to macrolides. Therefore, isolates that are resistant to macrolides but susceptible to clindamycin under standard testing should be tested to methylase mediated clindamycin resistance via the D-zone test. Other mechanisms include increased activation of an efflux pump and destruction of the drug.
Antimicrobial Spectra of Lincosamides in Animals
Lincomycin has a limited spectrum against aerobic pathogens but a fairly broad spectrum against anaerobes. Clindamycin is a more active analogue with somewhat different pharmacokinetic patterns, with increased activity against anaerobes and Staphylococcus aureus. Clindamycin also has activity against some protozoa, including Toxoplasma gondii. Many gram-positive cocci, except for enterococci, and Mycoplasma are inhibited by lincosamides; however, most gram-negative organisms are resistant.
Clindamycin is less effective toward ureaplasmas. Bacteroides spp and other anaerobes are usually susceptible. Clostridium difficile strains appear to be regularly resistant.
Absorption of Lincosamides in Animals
Lincomycin is incompletely absorbed from the GI tract in nonherbivorous species; plasma concentrations peak within 2–4 hours. Absorption from IM injection sites is good; plasma concentrations peak in 1–2 hours. Approximately 90% of an oral dose of clindamycin is absorbed, and effective plasma concentrations are achieved more rapidly than with lincomycin. Absorption may be affected by the ingestion of food. Clindamycin palmitate is administered PO, and clindamycin phosphate IM; the latter reaches peak plasma concentration in 1–3 hours.
Distribution of Lincosamides in Animals
Lincosamides are highly lipid soluble, leading to wide distribution in many fluids and tissues, including bone; however, notable concentrations are not attained in the CSF even when the meninges are inflamed. Poor CSF concentrations are due to the high degree of plasma-protein binding and rapid elimination kinetics. They diffuse across the placenta in many species. Approximately 90% of clindamycin is bound to plasma proteins. It also accumulates in polymorphonuclear WBCs and alveolar macrophages such that concentrations exceed those of plasma 50-fold. Clindamycin is able to penetrate glycocalyx, such as that associated with dental tartar.
Lincosamides diffuse across the placenta in many species. Due to the basic nature of lincosamides, accumulation occurs in acidic tissues such as abscesses, the prostate, or the udder, which can result in prolonged milk residues.
Biotransformation of Lincosamides in Animals
After administration PO, ~50% of a dose of lincomycin and 80%–90% of a dose of clindamycin are metabolically altered in the liver. Metabolites often retain activity. Liver disease impairs the biotransformation of lincosamides, and therefore dose alterations should be considered in these cases.
Excretion of Lincosamides in Animals
Unchanged lincosamides and several metabolites may be excreted in bile and urine. In people, as little as 10% of clindamycin is excreted in the urine. The proportions depend on the route of administration. Concentrations remain high in the feces for some days, and growth of sensitive microorganisms in the large intestine may be suppressed for up to 2 weeks. Milk is also an important excretory route.
Pharmacokinetic Values of Lincosamides in Animals
The elimination half-life of lincosamides is frequently >3 hours, and the apparent volume of distribution is >1 L/kg. They are usually administered every 12 hours. In dogs, clindamycin has an elimination half-life of 3.9 hours and a volume of distribution of 1.4 L/kg.
Therapeutic Indications and Dose Rates
The lincosamides are indicated for infections due to susceptible gram-positive organisms, particularly streptococci and staphylococci, and for those due to anaerobic pathogens. Clindamycin is approved for use in cats and dogs for treatment of infected wounds, abscesses, and dental infections. It is frequently used in the treatment of postsurgical orthopedic infections. Clindamycin has also been administered to treat selected protozoal diseases, including toxoplasmosis, but usually in combination with other antimicrobials.
Special Clinical Concerns
Adverse Effects and Toxicity of Lincosamides in Animals
No serious organ toxicity from lincosamides has been reported, but GI disturbances may occur in all species. Adverse effects are relatively infrequent in dogs and cats but are very serious in herbivores. Clindamycin-induced pseudomembranous enterocolitis (due to toxigenic C difficile) or lincosamide-induced disruption of GI flora is a serious adverse reaction in a number of species and can be lethal; thus, lincosamides are contraindicated for use in horses, guinea pigs, hamsters, rabbits, chinchillas, and ruminants. Hypersensitivity reactions occasionally are seen. Lincosamides should not be used in neonates because of their limited ability to metabolize drugs.
Administration of clindamycin without food or water has resulted in esophagitis as well as esophageal ulceration and stricture in cats. Lincosamides exhibit peripheral neuromuscular blockade and cardiodepressive effects and therefore should not be given with anesthetics or via rapid IV bolus. Intramuscular injections may lead to injection site reactions and pain. Dose reduction should be considered in patients with hepatic insufficiency.
Interactions With Lincosamides in Animals
Lincosamides have additive neuromuscular effects with anesthetic agents and skeletal muscle relaxants. Kaolin-pectin prevents their absorption from the GI tract. They should not be combined with bactericidal agents or with the macrolides. Clindamycin is synergistic with metronidazole against B fragilis.
Effects of Lincosamides on Laboratory Tests in Animals
Lincosamides may increase activities of alkaline phosphatase, AST, and ALT.
Drug Withdrawal Times of Lincosamides in Animals
Although not prohibited from extralabel drug use, lincomycin and clindamycin are not approved for use in ruminants in the US, and therefore there is zero tolerance for meat or milk residues. Lincomycin is approved for use in swine, chickens, and honeybees in the US. Clindamycin does not carry any food-producing animal approvals in the US. Pirlimycin is only approved for intramammary use in cattle in the US.
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 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, www.farad.org) for withdrawal recommendations.