Macrolides and Lincosamides

Erythromycin and oleandomycin are examples with a 14-membered ring. The former is a mixture of three closely related compounds erythromycin A, B, and C erythromycin A is the major and most important component. The latter consists of a single component. 

Spiramycin, kitasamycin, josamycin, desmycosin, mirosamycin, tilmicosin, and tylosin are examples with a 16-membered ring. Spiramycin consists of three components spiramycin I, II, and III spiramycin I is the major component. Kitasamycin consists of several components leucomycin Ai, A3 9, and A, the leucomycin A5 being the major component (89). losamycin is identical to the leucomycin A3 (90), while tylosin consists of four components, tylosin A, B, C, and D, the major component being tylosin A. Tylosin B is identical to desmycosin. 

Sedecamycin is an example with a 17-membered ring that belongs to the lankacidin group of antibiotics. It is a neutral compound since, unlike other macro-lides containing amino sugars, sedecamycin does not contain amino sugar moieties (93). 

Macrolide antibiotics target the bacterial ribosome and inhibit the bacterial protein biosynthesis. Many gram-negative bacteria are inherently resistant to mac-rolides because their outer membrane is impermeable to macrolides. Several mechanisms of acquired resistance have been reported. In some cases, resistance is conferred by methylation of ribosomes by methylase enzymes, the genes of 

In general, the macrolides are administered orally but sometimes also paren-terally. All the members of this group are well absorbed and are distributed extensively in tissues, especially in the lungs, liver, and kidneys, with high tissue to plasma ratios. They are retained in the tissues for long periods after the levels in the blood have ceased to be detectable. Elimination of all macrolides occurs primarily through hepatic metabolism, which accounts for approximately 60% of an administered intravenous dose the remainder is excreted in active form in the urine and bile. With oral and intramuscular administration, urinary excretion decreases, but biliary excretion and hepatic metabolism increase proportionally. Milk has often macrolide concentrations severalfold greater than in plasma (7). 

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The tetracyclines exert their effect by inhibiting bacterial protein syndiesis, which is a process necessary for reproduction of die microorganism. The ultimate effect of diis action is tiiat the bacteria are either destroyed or dieir multiplication rate is slowed. The tetracyclines are bacteriostatic (capable of slowing or retarding die multiplication of bacteria), whereas die macrolides and lincosamides may be bacteriostatic or bactericidal (capable of destroying bacteria). 

SUMMARY DRUG TABLE TETRACYCLINES, MACROLIDES AND LINCOSAMIDES... 

An ongoing assessment is important during therapy widi die tetracyclines, macrolides, and lincosamides. The nurse should take vital signs every 4 hours or as ordered by die primary health care provider. The nurse must notify the primary health care provider if tiiere are changes in the vital signs, such as a significant drop in blood pressure, an increase in die pulse or respiratory rate, or a sudden increase in temperature. 

ORAL ADMINISTRATION. To control the infectious process or prevent a bacterial infection, the nurse must keep several important things in mind when administering the tetracyclines, macrolides, and lincosamides. 

Macrolides and lincosamides have the same receptor site. They bind to the bacterial 50s ribosomal subunit, inhibiting protein synthesis and hence cell growth. Macrolides are usually bacteriostatic at low concentrations, but can become bactericidal for sensitive strains at high concentrations. 

Figure 1.6 Number of antibiotic prescriptions per 1000 inhabitants per antibiotic anatomical therapeutic chemical (ATC) classification in 13 European countries in 1997. In parentheses are the ATCs used by the WHO. Tet = tetracyclines, Pen = penicillin, Ex-Pen = extended-spectrum penicillins, B-Lac = (3-lactamase-sensitive penicillins. Cep = cephalosporins, TMP = trimethoprim (alone or in combination), Mac + Lin = macrolides and lincosamides, Mac = macrolides, Lin = lincosamides. Ami = aminoglycosides, and Qui = quinolone. The 13 countries are SP = Spain, GR = Greece, BG = Belgium, PR = Prance, PL = Portugal, IT = Italy, PI = Pinland, UK = United Kingdom, DE = Denmark, AU = Austria, GE = Germany, SW = Switzerland, and NL = Netherlands. (Based on data from Molstad et al., 2002.)...

Fig. 3.4 Chemical structures of commonly used macrolides and lincosamides.

Macrolide and lincosamide antibiotics are weakly basic compounds slightly soluble in water but readily soluble in common organic solvents. They are most composed of several closely related components that may vary in proportion depending upon the source of the formulation. Macrolides other than oleandomycin are stated to be unstable at both acidic and basic aqueous solutions. 

For the analysis of macrolide and lincosamide residues in liquid foods such as milk, a pretreatment step for fat removal carried out by centrifugation (133-135) is usually required. Semisolid food samples such as muscle, kidney, and liver require often more intensive sample pretreatment including a mincing and/or a homogenization step for breaking up tissue. 

For efficient extraction of macrolide and lincosamide residues from edible animal products, bound residues should be rendered soluble, most if not all of the proteins should be removed, and high recoveries for all analytes should be provided. Since tliese antibiotics do not strongly bind to proteins, many effective extraction methods have been reported. Sample extraction/deproteinization is usually accomplished by vortexing liquid samples or homogenizing semisolid samples with acetonitrile (136—139), acidified (136,140-142) orbasified acetonitrile (143), methanol (14, 144, 145), acidified (145-147) or basified methanol (148), chloroform (149-151), or dichloromethane under alkaline conditions (152). However, for extraction of sedecamycin, a neutral macrolide antibiotic, from swine tissues, use of ethyl acetate at acidic conditions has been suggested (153), while for lincomycin analysis in fish tissues, acidic buffer extraction followed by sodium tungstate deproteinization has been proposed (154). 

Cleanup of macrolides and lincosamides from coextracted material can also be accomplished with solid-phase extraction columns. Nonpolar sorbents such as XAD-2 resin (148) or reversed-phase sorbents (133, 134, 137, 141, 142) are usually employed in solid-phase extraction. In the latter case, ion-pairing with pentanesulfonic acid can also be applied for enhancing retention onto the hydro-phobic Ci8 material (154). However, these sorbents are not always effective for efficient cleanup of liver and kidney extracts. The basic character of macrolides and lincosamides suggests that cation-exchange sorbents such as aromatic-sulfonic acid (145,147), or polar sorbents such as silica (144,152,153), aminopropyl (139), or diol (149-151), can be powerful alternative approaches for isolation and/or cleanup of these compounds. 

At present, methods based on liquid chromatography are most widely used for determining macrolides and lincosamides in biological samples (Fig. 29.4). 

In liquid chromatographic analysis of macrolides and lincosamides, most popular is the ultraviolet detector (Table 29.4). Tylosin, tilmicosin, spiramycin, sedecamycin, and josamycin exhibit relatively strong ultraviolet absorption, but erythromycin, lincomycin, pirlimycin, and oleandomycin show extremely weak absorption in the ultraviolet region. Hence, detection at 200-210 nm has been reported for the determination of lincomycin (146). However, a combination of poor sensitivity and interference from coextractives necessitated extensive cleanup and concentration of the extract. Precolumn derivatization of pirlimycin with 9-fluorenylmethyl chloroformate has also been described to impart a chromophore for ultraviolet detection at 264 nm (140). 

Electrochemical detection is better suited to the analysis of erythromycin and lincomycin. This method of detection has been applied for the determination of erythromycin A (139) and lincomycin (154) residues in salmon tissues. Liquid chromatography coupled with mass spectrometry is particularly suitable for confirmatory analysis of the nonvolatile macrolides and lincosamides. Typical applications of this technique are through thermospray mass spectrometry, which has been used to monitor pirlimycin in bovine milk and liver (141,142), and chemical ionization, which has been applied for identification of tilmicosin (151) in bovine muscle, and for identification of spiramycin, tylosin, tilmicosin, erythromycin, and josamycin residues in the same tissue (150). 

Table 29.4 Physicochemical Methods for Macrolide and Lincosamide Antibacterials in Edible Animal Products... 

Karlsson M, Fellstrom C, Heldtander MU, Johansson KE, Franklin A. Genetic basis of macrolide and lincosamide resistance in Brachyspira (Serpulina) hyodysenteriae. FEMS Microbiol Lett 1999 172(2) 255-60. 

The macrolide antibiotics include erythromycin, clarithromycin, azithromycin, tylosin, tilmicosin and tiamulin. Clindamycin and lincomycin are related lincosamides. Susceptible bacteria include staphylococci, streptococci, Campylobacter jejunii, Clostridium spp., R. equi, Mycoplasma pneumoniae and Chlamydia spp. Drugs in this group are only effective against a few Gram-negative bacteria in cattle, namely some strains of Pasteurella and Haemophilus spp. Macrolides and lincosamides are associated with causing colitis in horses, so their use is usually restricted to p.o. erythromycin for the treatment of R. equi infections in foals. Subantimicrobial doses of erythromycin are administered i.v. to horses for gastrointestinal prokinetic action. 

Inhibition of protein synthesis through an action on certain subunits of microbial ribosomes (aminoglycosides, tetracyclines, chlorampenicol and its derivatives, macrolides and lincosamides). Each class of antimicrobial agent attaches to a different receptor site apart from macrolides and lincosamides, which bind to the same site on the 50S subunit of the microbial ribosome. 

In recent years, new resistance phenotypes (macrolide and streptogramin B antibiotics [MS] or partial macrolide and streptogramin B antibiotics [PMS], and macrolide antibiotics [M]) have been observed in elinical isolates of staphylococci and streptococci. Ross et al. [61, 125, 193] and Goldman and Capobianco [126] reported that MS-resistant strains of Staphylococcus epidermidis were resistant to 14- or 15-membered-ring macrolides and streptogramin B, but were susceptible to 16-membered-ring macrolide and lincosamide antibiotics. 

This chaj)ter discusses three groups of broad-spectrum antibiotics the tetracyclines, tlie macrolid, and the lincosamides. Example of the tetracycline include doxycycline (Vibramycin), minocycline (Minocin), and tetracycline (Sumycin). Examples of the macrohde include azithromycin (Zitliromax), clarithromycin (Biaxin), and erytliromycin (E-Mycin). The lincosamides include clindamycin (Cleocin) and lin-comycin (Lincocin). The Summary Drug Table Tetracyclines, Macrolide, and Lincosamide describe the lyi es of broad-spectrum antibiotics discussed in tliis chapter. 

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