These drugs have different chemical structures but are clinically very similar in their pharmacokinetics and spectrum of action. They are all bacteriostatic.
Macrolides include erythromycin, tylosin, tilmicosin and spiramycin (less active) which are commonly used in animals; oleandomycin is sometimes used in people. Roxithromycin, clarithromycin and azithromycin are new human drugs which look promising (better pharmacokinetics). Kitsamycin is used in animals in Australia.
Lincosamides are chemically different but clinically identical to macrolides. Lincomycin and pirlimycin are used in animals, clindamycin in people.
Pleuromutilins are also very similar. Tiamulin is the only drug used in NZ, but valnemulin is used in Europe. This class of drugs is not used in people.
These drugs bind to the 50S bacterial ribosomal subunit and inhibit peptide chain elongation by inhibition of translocation and movement along the mRNA. Some of the drugs bind at several places.
The macrolides have recently been shown to have some anti-inflammatory effect - preventing superoxide and cytokine production and stabilising macrophages and T cells. This may be a useful side effect in respiratory and skin infections.
Erythromycin acts as a prokinetic in the bowel by several mechanisms (see gut pharmacology notes).
These drugs have a narrow spectrum mainly confined to Gram positive bacteria, including penicillinase producing staphs, but not enterococci. They are also active against Pasteurella and Bacteroides spp, Mycoplasma spp and Rickettsia spp. Tylosin and roxithromycin are used clinically against Mycoplasma, Chlamydia and some spirochaetes (Treponema and Moraxella). Tiamulin is effective in swine dysentery (Brachyspira hyodysenteriae). Most strains are now resistant to tylosin. Erythromycin is effective against Rhodococcus equi in foals. Macrolides (especially erythromycin) are used in people for severe Campylobacter infections, but resistance is high and increasing (particularly around Auckland). Roxithromycin and azithromycin have some activity against protozoa such as Toxoplasma gondii. Lincosamides, particularly clindamycin, have useful activity against anaerobes.
Chromosomal resistance occurs readily. Plasmid mediated resistance is also common. Resistance usually involves changes to the 50S ribosomal unit which prevents drug binding. This occurs very quickly with lincosamides and slowest with tiamulin.
Cross resistance amongst the macrolides, lincosamides and streptogramin Bs is common but not complete. Cross resistance with pleuromutilins is less likely as they have three binding sites.
Macrolides are generally safe. Some local reactions occur at the site of injection, especially thrombophlebitis after intravenous injection. Horses tend to get gastrointestinal disturbances due to enterohepatic circulation and the antibiotic effect on the normal flora. Tylosin is contraindicated in the horse for this reason.
Dogs and cats often get gut upsets and vomiting after erythromycin (it increases gut motility (see gut notes)).
Tilmicosin is cardiotoxic and must not be given iv, although arrhythmias have been reported with most of these drugs in people.
Tiamulin in combination with coccidiostats will cause severe growth depression (mainly important in pigs).
Transient deafness has been reported in people.
The macrolides are organic bases. Erythromycin’s pKa is 8.6 and tylosin’s pKa is 7.1 so their action is favoured by higher pH.
Erythromycin is absorbed poorly after oral administration, but distributes well to many tissues, achieving higher tissue concentrations than plasma. This is especially true for bone. Macrolides are also taken up by phagocytes. They do not penetrate the intact blood brain barrier. Ion trapping ensures that macrolides achieve high concentration in normal milk, but the raised pH of mastitic milk reduces the benefit of this effect.
Macrolides are found in saliva at high concentrations. One product (Stomorgyl) is a combination of the macrolide spiramycin with the nitroimidazole metronidazole. This product is marketed strongly on the basis of saliva penetration.
Macrolides undergo extensive enterohepatic circulation. They are largely metabolised and only small amounts can be found in the urine or the faeces.
Lincosamides are rapidly and almost completely absorbed after oral administration with peak plasma levels occurring within 2 hours. Clindamycin is better absorbed than lincomycin.
Clindamycin is 90 - 95% plasma protein bound. It is distributed widely, but is not concentrated in any particular tissue. It does cross inflamed meninges and passes into bone, achieving about 40% of plasma concentration in these tissues (humans). Liver metabolism produces active and inactive metabolites. Most drug is eliminated by the liver, with only 8 - 20 % being excreted in the urine.
Azithromycin has a very long half life (35h) in cats so is usually given as a single dose.
Erythromycin is acid labile and must therefore be administered as enteric coated tablets, or parenterally. Estolate and stearate salts are used to enhance absorption. Newer macrolides such as roxithromycin have been designed to overcome this problem.
Tylosin is available as a powder for mixing with drinking water. This is used especially in the poultry industry. Tylosin is also available as parenteral preparations in some countries. It has been banned in Europe as a growth promoter.
Erythromycin has traditionally been used as a subtitute for penicillin in people who are allergic to penicillin. It was also used to treat Campylobacter, but overuse as part of a protocol for Helicobacter means that many strains of Campylobacter in NZ are now resistant.
Azithromycin is usually reserved for chlamydial infections, but has been used in antimalarial combinations with chloroquine. Clarithromycin has some effect against TB, and is included in some protocols for multiresistant TB.
The 3-ketolides are a new related group of drugs which look promising. Telithromycin has been licensed for human use overseas and appears effective against erythromycin resistant Strep pneumoniae.
