Lincosamides

Lincomycin and clindamycin bind exclusively to the 50S subunit of bacterial ribosomes and suppress protein synthesis. Lincosamides, macrolides, and chloramphenicol, although not structurally related, seem to act at this same site. The lincosamides are bacteriostatic or bactericidal depending on the concentration. Activity is enhanced at an alkaline pH. Efficacy is considered time dependent.

Lincosamides are generally ineffective against facultative anaerobic (but not anaerobic) gram-negative bacteria. 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 streptogramins. Other mechanisms include increased activation of an efflux pump and destruction of the drug.

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. Many gram-positive cocci, except for enterococci, and Mycoplasma are inhibited by lincosamides, but 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.

Lincomycin is incompletely absorbed from the GI tract, especially if administered soon after feeding; plasma concentrations peak within 2–4 hr. Absorption from IM injection sites is good; plasma concentrations peak in 1–2 hr. Approximately 90% of an oral dose of clindamycin is absorbed, and effective plasma concentrations are achieved more rapidly than with lincomycin. Absorption is not significantly affected by the ingestion of food. Clindamycin palmitate is used PO, and clindamycin phosphate IM; the latter reaches peak plasma concentration in 1–3 hr.

Lincosamides are widely distributed in many fluids and tissues, including bone, but significant concentrations are not attained in the CSF even when the meninges are inflamed. 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.

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.

Unchanged antibiotic 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 wk. Milk is also an important excretory route.

The elimination half-life of lincosamides is frequently >3 hr, and the apparent volume of distribution is >1 L/kg. They are usually administered bid. In dogs, clindamycin has an elimination half-life of 3.9 hr and a volume of distribution of 1.4 L/kg.

No serious organ toxicity has been reported, but GI disturbances do occur. Clindamycin-induced pseudomembranous enterocolitis (caused by toxigenic Clostridium difficile) or disruption of GI flora is a serious adverse reaction in a number of species and can be lethal; thus, clindamycin is contraindicated for use in some in horses, guinea pigs, hamsters, rabbits, chinchillas, and ruminants. Lincosamides are contraindicated in horses, because severe and even fatal colitis may develop. Skeletal muscle paralysis may be seen at high concentrations. Hypersensitivity reactions occasionally are seen. Lincosamides should not be used in neonates because of their limited ability to metabolize drugs.

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.

Alkaline phosphatase, AST, and ALT may be increased.

In several countries, there is a 2-day withdrawal time for pigs.