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
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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 63a
a EU
withdrawal. Withdrawal period for USA (35 days) pending; withdrawal period for
Canada is 49 days.
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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.
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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.
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