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Chapter: Modern Pharmacology with Clinical Applications: Bacitracin, Glycopeptide Antibiotics, and the Polymyxins

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Glycopeptides: Vancomycin and Teicoplanin

Vancomycin (Vancocin) is a complex tricyclic glycopep-tide antibiotic produced by Streptomyces orientalis, while teicoplanin (Targocid) is derived from Actino-planes (Actinomyces) teichomyceticus.

GLYCOPEPTIDES: VANCOMYCIN AND TEICOPLANIN

 

 

Structure and Mechanism of Action

 

Vancomycin (Vancocin) is a complex tricyclic glycopep-tide antibiotic produced by Streptomyces orientalis, while teicoplanin (Targocid) is derived from Actino-planes (Actinomyces) teichomyceticus. Teicoplanin has two major components: a phosphoglycolipid (A1) and five chlorine-containing glycopeptides (A2). It is avail-able as an investigational drug.

 

The glycopeptides are inhibitors of cell wall synthesis. They bind to the terminal carboxyl group on the D-alanyl-D-alanine terminus of the N-acetylglucosamine-N-acetylmuramic acid peptide and prevent polymeriza-tion of the linear peptidoglycan by peptidoglycan synthase. They are bactericidal in vitro.

 

Antimicrobial Spectrum

 

The glycopeptides are narrow-spectrum agents that are active against gram-positive organisms. Like van-comycin, teicoplanin is bacteriostatic against staphylo-cocci, streptococci, and enterococci. Gram-positive rods, such as Bacillus anthracis, Corynebacterium diph-theriae, Clostridium tetani, and Clostridium perfringens, are also sensitive to the glycopeptides. The glycopep-tides are not effective against gram-negative rods, my-cobacteria, or fungi.

 

Absorption, Distribution, and Excretion

 

Vancomycin is poorly absorbed from the gastrointesti-nal tract, resulting in high concentrations in the feces. In neutropenic patients and others with altered gastroin-testinal mucosa with denudation, significant oral ab-sorption of vancomycin may occur and may be accom-panied by additive toxicity if rapid infusion or large parenteral doses of the drug are given concomitantly. Except for the treatment of staphylococcal enterocolitis and pseudomembranous colitis, it is administered intra-venously. Peak serum levels are achieved 2 hours after intravenous (IV) administration, and about 55% is bound to serum protein. The therapeutic range is a trough concentration between 5 and 15  μg/mL, and the peak should stay below 60  μg/mL to avoid side effects. In normal adults the serum half-life is 5 to 11 hours. With impaired renal function, the half-life is 7 to 9 days. The dose of vancomycin must be carefully adjusted to avoid toxicity or ineffective treatment, especially in pa-tients undergoing hemodialysis. Pediatric oncology pa-tients with normal renal function may require van-comycin dosage regimens that are substantially greater than predicted. Similar studies in adult patients with hematological malignancies have suggested a larger dosage requirement as well, owing to an increased vol-ume of distribution.

 

After IV administration, vancomycin diffuses into serous cavities and across inflamed but not normal meninges. It can be used in the treatment of meningitis with susceptible organisms. It is also given via ventricu-loatrial or ventriculoperitoneal shunts when these be-come infected.

 

Renal excretion is predominant, with 80 to 90% of an administered dose eliminated in 24 hours. Only small amounts appear in the stool and bile after intravenous administration.

 

Teicoplanin, like vancomycin, is not absorbed from the intestinal tract. Peak plasma levels are achieved about 2 hours after intramuscular administration. The drug distributes widely in tissues; plasma protein binding is about 90%. The half-life approximates 50 hours, which is considerably longer than that of vancomycin, and may make it useful for outpatient administration. Like van-comycin, teicoplanin is excreted by the kidneys.

 

Clinical Uses

 

Vancomycin and teicoplanin display excellent activity against staphylococci and streptococci, but because of the wide availability of equally effective and less toxic drugs, they are second-line drugs in the treatment of most infections. As antistaphylococcal agents they are less effective than β-lactam cephalosporin antibiotics, such as nafcillin and cefazolin. They have attained much wider use in recent years as a consequence of the emer-gence of methicillin-resistant S. aureus (MRSA) infec-tions, in particular the growing importance of Staph-ylococcus epidermidis infections associated with the use of intravascular catheters and in patients with peri-tonitis who are on continuous ambulatory peritoneal dialysis.

 

Vancomycin is also an effective alternative therapy for the treatment of staphylococcal enterocolitis and en-docarditis. The combination of vancomycin and either streptomycin or gentamicin acts synergistically against enterococci and is used effectively for the treatment or prevention of enterococcal endocarditis. Teicoplanin demonstrates similar synergy.

 

Staphylococcal vascular shunt infections in persons undergoing renal dialysis have been successfully treated with vancomycin. Vancomycin in oral form can also be used in patients in whom C. difficile colitis is not re-sponding to metronidazole.

 

Teicoplanin, although not available in the United States, has been used to treat a wide range of gram-posi-tive infections, including endocarditis and peritonitis. It is not as effective as the β-lactams, but its actions are similar to those of vancomycin against staphylococcal infections.

 

An increased prevalence of MRSA has resulted in a greater use of vancomycin for this disorder. High-grade resistance of pneumococci to penicillin may also neces-sitate vancomycin therapy. Enterococci that are resist-ant to vancomycin are emerging as major nosocomial pathogens. These strains are generally resistant to a number of other antibiotics, such as penicillin, ampi-cillin, and gentamicin, which limits treatment options. The possibility of transferring these resistance determi-nants to other gram-positive organisms, like S. aureus, is a valid concern. It is therefore necessary to limit the use of vancomycin to treatment of serious infections caused by methicillin-resistant staphylococci and situations in which allergies preclude the use of other antibiotics.

 

Adverse Effects

 

The major adverse effect associated with vancomycin therapy is ototoxicity, which may result in tinnitus, high-tone hearing loss, and deafness in extreme instances. More commonly, the intravenous infusion of van-comycin can result in chills, fever, and a maculopapular skin rash often involving the head and upper thorax (red man syndrome). Red man syndrome is associated with increased levels of serum histamine. Vancomycin is rarely nephrotoxic when used alone. Teicoplanin rarely causes red man syndrome or nephrotoxicity.

 

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