Macrolides

The antimicrobial mechanism seems to be the same for all of the macrolides. They interfere with protein synthesis by reversibly binding to the 50S subunit of the ribosome. They appear to bind at the donor site, thus preventing the translocation necessary to keep the peptide chain growing. The effect is essentially confined to rapidly dividing bacteria and mycoplasmas. Macrolides are regarded as being bacteriostatic but demonstrate bactericidal activity at high concentrations. Macrolides are significantly more active at higher pH ranges (7.8–8). Macrolides are considered to be time dependent in terms of antimicrobial efficacy.

The macrolides appear to have immunomodulatory effects useful to treat respiratory infections, in particular, those associated with Pseudomonas aeruginosa, based on efficacy at doses (concentrations) considered ineffective against susceptible bacteria.

Lack of cell wall permeability renders most gram-negative organisms inherently resistant to macrolides. There are a few exceptions, and gram-negative forms without cell walls are usually susceptible. Resistance to macrolides in gram-positive organisms results from alterations in ribosomal structure (target site methylation or mutation) and loss of macrolide affinity. Post-translational methylation results in cross-resistance to lincosamides and streptogramins. Macrolide resistance may be intrinsic or plasmid-mediated and constitutive or inducible; it may develop rapidly (erythromycin) or slowly (tylosin) and generally results in cross-resistance between macrolides. Efflux from cells is a second important mechanism of resistance for some members of this class, as is, less frequently, drug inactivation.

Macrolides are active against most aerobic and anaerobic gram-positive bacteria, although there is considerable variation as to potency and activity. In general, macrolides are not active against gram-negative bacteria, but some strains of Pasteurella, Haemophilus, and Neisseria spp may be sensitive. Exceptions include tilmicosin, gamithromycin, and tulathromycin, for which the spectra are characterized as broader and include Mannheimia haemolytica and Pasteurella multocida, as well as the above-mentioned gram-negative bacteria. Helicobacter also is generally included in the spectrum. Azithromycin, derived from erythromycin, includes Bordetella in its spectrum. Bacteroides fragilis strains are moderately susceptible to macrolides. Macrolides are active against atypical mycobacteria, Mycobacterium, Mycoplasma, Chlamydia, and Rickettsia spp but not against protozoa or fungi. In vitro synergism is seen with cefamandole (against B fragilis), ampicillin (against Nocardia asteroides), and rifampin (against Rhodococcus equi).

Macrolides are readily absorbed from the GI tract if not inactivated by gastric acid. Oral preparations are often enteric-coated, or stable salts or esters (such as stearate, lactobionate, glucoheptate, propionate, and ethylsuccinate) are used. Plasma concentrations peak within 1–2 hr in most cases, although absorption patterns may be erratic because of the presence of food and may depend on the salt or ester used. Absorption from the ruminoreticulum is usually delayed and is unreliable. Erythromycin and tylosin may also be administered IV or IM. Tilmicosin, gamithromycin, and tulathromycin are administered SC, except in swine, for which an oral tilmicosin preparation is available. Absorption after injection is rapid, but pain and swelling can develop at the injection sites.

Macrolides become widely distributed in tissues, and concentrations are about the same as in plasma, or even higher in some instances. They actually accumulate within many cells, including macrophages, in which they may be ≥20 times the plasma concentration. WBCs will then facilitate distribution to the site of inflammation. This accumulation accounts in part for the long dosing interval that characterizes some macrolides (eg, tilmicosin). With spiramycin, the tissue concentrations remain especially high, even though plasma concentrations are rather low. Macrolides tend to concentrate in the spleen, liver, kidneys, and particularly the lungs. They enter pleural and ascitic fluids and concentrate in the eye but do not distribute to the eye or the CSF (only 2%–13% of plasma concentration unless the meninges are inflamed). They concentrate in the bile and milk. Up to 75% of the dose is bound to plasma proteins, and they bind to α1-acid glycoproteins rather than to albumin.

Metabolic inactivation of the macrolides is usually extensive, but the relative proportion depends on the route of administration and the particular antibiotic. After administration PO, 80% of an erythromycin dose undergoes metabolic inactivation, whereas tylosin appears to be eliminated in an active form.

Macrolide antibiotics and their metabolites are excreted mainly in bile (>60%) and often undergo enterohepatic cycling. Urinary clearance may be slow and variable (often <10%) but may represent a more significant route of elimination after parenteral administration. For example, in people, 14% of azithromycin and 20%–40% of clarithromycin is excreted unchanged in urine. The concentration of macrolides in milk often is several times greater than in plasma, especially in mastitis.

Macrolides tend to be characterized by high oral bioavailability, but this is variable among species, drugs, and salts. For example, oral bioavailability for tylosin is 0.35 for the tartrate salt versus 0.14 for the phosphate. For azithromycin, oral bioavailability is 39% in foals 6–10 wk old, 59% in cats, and 97% in dogs. The accumulation of macrolides among different tissues contributes to the large volume of distribution (for azithromycin 12 L/kg in dogs, 23 L/kg in cats, 22 L/kg in foals 6–10 wk old) and long elimination half-life (for azithromycin, 29 hr in dogs, 35 hr in cats, and 20 hr in foals). For tulathromycin, the elimination half-life is 65 hr in calves and 69 hr in pigs 2–3 mo old. Because of these long half-lives, time to steady state may be prolonged, and a loading dose may be indicated for multiple dosing. Tylosin, however, is an exception, with a volume of distribution approximating 1 L/kg and a half-life of 1–2 hr. Another exception is azithromycin, which has a half-life in cats that varies among tissues, reaching >72 hr for some. Effective plasma inhibitory concentrations are maintained for ~8 hr after administration PO and for ~12–24 hr after IM injection. Dosage frequencies are commonly 2–3 times/day, PO, or 1–2 times/day, parenterally.

Toxicity and adverse effects are uncommon for most macrolides (except tilmicosin), although pain and swelling may develop at injection sites. Hypersensitivity reactions have occasionally been seen. Erythromycin estolate may be hepatotoxic and cause cholestasis; it may also induce vomiting and diarrhea, particularly when high doses are administered. Horses are sensitive to macrolide-induced GI disturbances that can be serious and even fatal. In pigs, tylosin may cause edema of the rectal mucosa, mild anal protrusion with diarrhea, and anal erythema and pruritus. After 5 mg/kg/day, dogs had a greater tendency to develop ventricular tachycardia and fibrillation during acute myocardial ischemia. Tilmicosin is characterized by cardiac toxicity (tachycardia and decreased contractility). Parenteral (but not oral) administration should be avoided in swine, and extra-label use should be avoided. Cattle have died after IV injection of tilmicosin, and human injury is possible after accidental exposure.

Macrolide antibiotics probably should not be used with chloramphenicol or the lincosamides, because they may compete for the same 50S ribosomal binding site, although the in vivo significance of this potential interaction is unclear. Activity of macrolides is depressed in acidic environments. Macrolide preparations for parenteral administration are incompatible with many other pharmaceutical preparations. Erythromycin and troleandomycin and other macrolides are microsomal enzyme inhibitors that depress CYP3A4 (in people) and thus the metabolism of many drugs. Macrolides also are substrates for and potentially potent inhibitors of P-glycoprotein efflux pumps.

Alkaline phosphatase, bilirubin, bromsulphthalein (BSP^®), total WBC count, eosinophil count, AST, and ALT may increase. Cholesterol concentrations may decrease.

Regulatory requirements for withdrawal times and milk discard times vary among countries. These should be followed carefully to prevent food residues and consequent public health implications. The withdrawal times listed in Drug Withdrawal and Milk Discard Times of Macrolides serve only as general guidelines. Tilmicosin is characterized by a 28-day withdrawal time and should not be used in any species other than adult cattle (but not in dairy cows >20 mo old).