MACROLIDES

The macrolide antibiotics clarithromycin and azithromycin have demonstrated in vitro activity against mycobacteria, although they have limited activity against M. tuberculosis. Clarithromycin is four times as active as azithromycin against M. aviumintracellulare in vitro. Azithromycin’s lower potency may be compensated for by its greater intracellular penetration and its two-fold higher tissue levels than plasma levels. Clarithromycin with azithromycin, in combination with other drugs, has gained an important role in the prevention and treatment of MAC in HIVinfected patients.

The 14-, 15- and 16-membered-ring macrolides share the same antibacterial spectrum, including most Gram-positive organisms, Neisseria spp., Haemophilus spp., Bordetella pertussis, Moraxella catarrhalis and both Gram-positive and Gramnegative anaerobes. They are inactive or poorly active against Enterobacteriaceae and non-fermentative Gramnegative bacteria such as Pseudomonas aeruginosa.

Widespread use of erythromycin and semisynthetic analogs has led to the emergence of resistance in Staphylococcus aureus, Streptococcus pneumoniae and Lancefield group A streptococci (Str. pyogenes). Chromosomal or plasmid- mediated resistance to erythromycin may be inducible or constitutive. Intrinsic resistance of Gram-negative bacilli is probably due to the relative impermeability of the outer membrane to the hydrophobic compounds and/or to an efflux mechanism of resistance.
Acquired resistance to macrolides involves three mechanisms: modification of the target, active efflux or inactivation. In the first type, a single alteration in 23S ribosomal RNA in the 50S ribosomal subunit confers cross-resistance to macrolides, azalides, lincosamides and streptograminB-type antibiotics (the so-called MLSB phenotype); the other types confer resistance to structurally related antibiotics only.
Modification of the 50S ribosomal targets is a complex mechanism. Several types have been described: ? Monomethylation of adenine 2058, located in the 23S rRNA, results in blockade of the N6 amino group of adenine and inhibition of binding of erythromycin A or its derivatives. It can be induced by 14-memberedring macrolides and azalides, but not by 16-memberedring macrolides or ketolides. Monomethylation or bimethylation of adenine 2058 or 2059 may be constitutive and affects all available macrolides. Monomethylation does not affect telithromycin.
? Mutation of adenine 2058 to guanine has been described in many bacterial species, such as staphylococci, streptococci (including Str. pneumoniae and Str. pyogenes), Helicobacter pylori, the M. avium complex and T. pallidum. Other point mutations on the peptidyltransferase site, such as adenine 2611 to guanine, lead to resistance to 14- and 15-membered-ring macrolides.
? Mutations at ribosomal proteins L4 and L22, which are close to the exit channel, have been reported in clinical isolates of Str. pneumoniae, Str. oralis and Str. pyogenes.An efflux pump, Mef, encoded by a mef gene, accounts for resistance in over 50% of Str. pneumoniae or Str. pyogenes isolates in certain geographic areas. It has been described in all streptococci, including the viridans group. Other pumps involved in macrolide resistance include Msr A/B in staphylococci, Acr-like in H. influenzae, Mre A in Str. agalactiae and Mtr (which also removes penicillin G) in N. gonorrhoeae.
Macrolide-inactivating esterases that hydrolyze the lactone ring are found mainly in Escherichia coli. Enzymes that fix either a glucose or a phosphate at the 2′ OH group of d- desosamine have been reported in Nocardia spp., which are resistant to all macrolides having a d-desosamine substituent. Inactivation mechanisms have also been reported in 16-membered-ring macrolides.
Oral absorption is rapid, with plasma peaks varying between 0.4 mg/L (azithromycin) and 11 mg/L (roxithromycin). Maximum concentrations are reached between 0.5 h (rokitamycin) and 3 h (clarithromycin) and are dose dependent.
The apparent elimination half-life varies from 1 h (miokamycin) to 44 h (dirithromycin); the absolute bioavailability varies between 10% (dirithromycin) and 55–60% (roxithromycin, clarithromycin). The main elimination route is via the bile and feces; a proportion of clarithromycin is excreted via the intestinal mucosa. A substantial part of the administered dose of clarithromycin is eliminated in urine. The long apparent elimination half-lives of roxithromycin, azithromycin and dirithromycin allow them to be administered as single daily oral doses.

The macrolides form a large group of closely related antibiotics produced mostly by Streptomyces and related species. They are characterized by a macrolactone ring (to which they owe their generic name), to which typically two sugars, one an amino sugar, are attached. The original macrolide complex, erythromycin A, was isolated in 1952 as a natural product of Saccharopolyspora erythraea (formerly Streptomyces erythreus). Other natural products followed. The search for analogs has focused on compounds with an extended antibacterial spectrum (notably against fastidious Gram-negative pathogens), improved pharmacokinetic properties (e.g. increased acid stability) and reduced gastrointestinal intolerance.
The most important therapeutic macrolides are characterized by a 14-, 15- or 16-membered lactone ring. Macrolides with a 12-membered ring are also known, but only as research compounds. In the group that includes erythromycin A, the lactone ring contains 14 atoms and one or two sugar groups attached by α- or β-glycosidic linkages to the aglycone. In the 16-membered-ring macrolides, two sugars are linked together and attached to the lactone ring through the amino sugar.
Insertion of a nitrogen atom into the erythronolide A ring of erythromycin A yielded a chemical subclass with a 15-membered ring, known as azalides, one of which, azithromycin, is used clinically. It shares the properties of other macrolide antibiotics, but exhibits increased potency against fastidious Gram-negative bacteria and some Enterobacteriaceae, and has a longer elimination half-life.
A further development came with the ketolides, semisynthetic derivatives of erythromycin A in which α-l cladinose at position 3 of the erythronolide A ring is replaced with a ketone function and a cyclic carbamate residue is present at C11–C12. Ketolides are highly stable, even at pH 1.0, and remain active against many erythromycin-resistant Gram-positive cocci. They do not induce resistance to macrolides, lincosamides and streptogramins caused by methylation of the ribosomal binding site . One such compound, telithromycin, is clinically available.
More than 100 other ketolide derivatives have been reported. Three – cethromycin, modithromycin and CEM 101 – are in clinical development at the time of writing. Modithromycin has a bicyclic bridge between positions 6 and 11 of the lactone ring, and because of this structure the name ‘bicyclolide’ has been proposed for this type of ketolide.
Several macrolides, including tylosin, mycinamycin, tilmicosin (a derivative of tylosin), tulathromycin and gamithromycin are used only in veterinary medicine and are not discussed further here.

Erythromycin is characterized by poor water solubility and rapid inactivation by stomach acidity, resulting in widely varying bioavailability after oral administration. Derivatives of erythromycin A have improved pharmacological properties, including bioavailability, gastrointestinal tolerance, higher peak plasma levels, longer apparent elimination plasma halflives and improved tissue concentrations.
Oral absorption is rapid, with plasma peaks varying between 0.4 mg/L (azithromycin) and 11 mg/L (roxithromycin). Maximum concentrations are reached between 0.5 h (rokitamycin) and 3 h (clarithromycin) and are dose dependent.
The apparent elimination half-life varies from 1 h (miokamycin) to 44 h (dirithromycin)： the absolute bioavailability varies between 10% (dirithromycin) and 55–60% (roxithromycin, clarithromycin). The main elimination route is via the bile and feces： a proportion of clarithromycin is excreted via the intestinal mucosa. A substantial part of the administered dose of clarithromycin is eliminated in urine. The long apparent elimination half-lives of roxithromycin, azithromycin and dirithromycin allow them to be administered as single daily oral doses.

The macrolides retain the classic clinical applications of erythromycin, including activity against Gram-positive cocci and intracellular pathogens such as Legionella, Chlamydia and Rickettsia spp. The improved pharmacokinetic properties and tissue distribution of some semisynthetic compounds may prove useful in more unusual settings such as infections due to mycobacteria (M. avium complex) and protozoa (e.g.Toxoplasma gondii, Entamoeba histolytica, Plasmodium falciparum). Other target infections are chronic gastritis (H. pylori) and borreliosis.

Macrolides are generally safe and serious adverse events are rare. A notable exception is erythromycin estolate, which is hepatotoxic and may cause severe hepatitis, probably as a result of the mixture of lauryl sulfate and the 2′-propionyl ester. Gastrointestinal complaints (nausea, vomiting, abdominal pain or, less frequently, diarrhea) are most common; they present a problem mainly with erythromycin doses higher than those recommended and are partly due to a hemiketal degradation product that acts on motilin, an intestinal endopeptide.
The semisynthetic 14- and 15-membered-ring macrolides are more acid stable than erythromycin A and are better tolerated.