MACROLIDES

MACROLIDES

The macrolide antibiotics typically have a large lactone ring in their structure and are much more effective against gram-positive than gram-negative  bacteria. They are also active against mycoplasmas and some rickettsiae.

Classes

Macrolides fall into 3 classes, depending on the size of the lactone ring.

None of the 12-membered ring group is used clinically.

Erythromycin and the closely related oleandomycin and troleandomycin belong to the 14-membered ring group.

Azithromycin and gamithromycin are 15-ring members, a subclass referred to as azalides.

Of the 16-membered ring group, spiramycin, josamycin, tylosin, and tilmicosin (synthesized from tylosin), are used clinically.

Tulathromycin contains 3 amine rings and is classified as a triamilide.

Macrolides

Erythromycin (obtained from Streptomyces erythreus)

Oleandomycin (obtained from Streptomyces antibioticus)

Spiramycin (S. ambofaciens)

Tylosin (S. fradiae)

            semi-synthetic derivatives of erythromycin

Clarithromycin (Biaxin)                     

Azithromycin (Zithromax; Zitromax)

Roxithromycin (Rulid)

Dirithromycin (Dynabac)

5% of penicillin susceptible strains are macrolides resistant; 50% Penn resistant strains may be resistant to macrolides

Ketolides (Telithromycin)

Macrolides in Veterinary Medicine

•         14 member ring - erythromycin

•         16 member ring - tylosin, tilmicosin

General Properties

•         A macrolide is actually a complex mixture of closely related antibiotics that differ from one another with respect to the chemical substitutions on the various carbon atoms in the structure, and in the aminosugars and neutral sugars.

•         For example, erythromycin is mostly erythromycin A, but B, C, D, and E forms may also be included in the preparation.

•         The macrolide antibiotics are colorless, crystalline substances.

•         They contain a dimethylamino group, which makes them basic.

•         Although they are poorly water soluble, they do dissolve in more polar organic solvents.

•         Macrolides are often inactivated in basic (pH >10) as well as acidic environments (pH <4 for erythromycin).

•         The multiple functional groups make it possible for them to undergo a large number of chemical reactions.

•         More stable ester forms are commonly used in pharmaceutical preparations - eg, acetylates, estolates, lactobionate, succinates, propionates, and stearates.

Antimicrobial Activity

Mode of Action

•         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 at high concentrations demonstrate bactericidal activity. Macrolides are significantly more active at higher pH ranges (7.8–8).

Bacterial Resistance

•         Resistance to macrolides in gram-positive organisms results from alterations in ribosomal structure and loss of macrolide affinity. The resistance may be intrinsic or plasmid-mediated and constitutive or inducible; it may develop rapidly (erythromycin) or slowly (tylosin). Cross-resistance between macrolides has been reported. Gram-negative organisms are probably resistant because macrolides cannot penetrate their cell walls. There are a few exceptions, and gram-negative forms without cell walls are usually sensitive.

Antimicrobial Spectra

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 where the spectra are characterized as broad and include Mannheimia haemolytica and Pasteurella multocida, as well as the above mentioned gram-negative bacteria. 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 Bacteroides fragilis), ampicillin (against Nocardia asteroides), and rifampin (against Rhodococcus equi).

Pharmacokinetic Features

Absorption

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 due to 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. Absorption after injection is rapid, but pain and swelling can develop at the injection sites.

Distribution

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. 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 but not 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.

Biotransformation

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.

Excretion

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. The concentration of macrolides in milk often is several times greater than in plasma, especially in mastitis.

Pharmacokinetics

Macrolides tend to be characterized by high bioavailability. The plasma half-lives of macrolides usually are 1–3 hr, and apparent volumes of distribution of 1,000–2,500 mL/kg reflect the extensive tissue distribution. An exception is azithromycin, which has a half-life in cats that varies among tissues, reaching more than 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.

Therapeutic Indications and Dose Rates

•         The macrolides are used to treat both systemic and local infections.

•         They are often regarded as alternatives to penicillins for the treatment of streptococcal and staphylococcal infections.

•         General indications include upper respiratory tract infections, bronchopneumonia, bacterial enteritis, metritis, pyodermatitis, urinary tract infections, arthritis, and others.

•         Formulations for treating mastitis are also available and often have the advantage of a short withholding time for milk.

•         Tilmicosin, gamithromycin, and tulathromycin are approved for use in the treatment of bovine respiratory diseases associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni.

Dosages of Macrolides

Macrolide                   Species            Dosage, Route, and Frequency

Erythromycin            Cattle              8–15 mg/kg, IM, sid-bid

                                    Cats                 15 mg/kg, PO, tid

                                    Foals                25 mg/kg, IM, tid

Tylosin                        Cattle              10–20 mg/kg, IM, sid-bid

                                    Pigs                 10 mg/kg, IM, sid-bid

                                                            7–10 mg/kg, PO, tid

                                    Cats                 10 mg/kg, IM, bid

Tilmicosin                   Cattle              10 mg/kg, SC, once

Tulathromycin           Cattle              2.5 mg/kg, SC, once

                                    Swine              2.5 mg/kg, IM, once

Gamithromycin         Cattle              6 mg/kg, SC, once

Special Clinical Concerns

Adverse Effects and Toxicity

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).

It is contraindicated in swine and should not be used in an extra-label manner.

Cattle have died after IV injection of tilmicosin; human deaths have occurred after accidental exposure.

Interactions

•         Macrolide antibiotics probably should not be used with chloramphenicol or the lincosamides because they may compete for the same 50 S 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 are microsomal enzyme inhibitors that depress the metabolism of some drugs.

•         Combination of OTC  and oleandomycin in 2:1 ratio administered by IM / IV route strengthen tha activity against G +ve orgs.

Effects on Laboratory Tests

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

Drug Withdrawal and Milk Discard Times of Macrolides

Macrolide                   Species                        Withdrawal Time      Milk Discard                                                                                      (days)                          Time (hr)

Erythromycin              Cattle                          14                                36–72

                                    Pigs                             7

Tylosin                        Cattle                          21                                96

                                    Pigs                             14

Tilmicosin                    Cattle                          28                                0

Tulathromycin             Cattle                          18                               

                                    Swine                          5

Gamithromycin           Cattle                          63^a

^a EU withdrawal. Withdrawal period for USA (35 days) pending; withdrawal period for Canada is 49 days.

•         Spriamycin – Drug of choice in the Rx of contagious bovine pleuropneumonia; Toxoplasmosis in ewes; ovine ricketssial keratoconjunctivitis, CRD in poultry, Swine dyscentery caused by Treponema hyodysentriae.

•         Tylosin – Cattle: Pneumonia, foot rot and metritis; Pigs: Swine dyscentery and pneumonia; Dogs and cats: Respirtory and urinary tract infections, otitis externa, metritis, leptospirosis; Poultry: CRD and infective sinusitis in turkeys

•         Tilmicosin - Mainly used in the Rx of bovine respiratory diseases associated with P. haemolytica.