Glycopeptide Antibiotics

GLYCOPEPTIDE ANTIBIOTICS

VANCOMYCIN

Vancomycin is an antibiotic produced by Streptococcus orientalis and Amycolatopsis orientalis. With the exception of Flavobacterium, it is active only against gram-positive bacteria. Vancomycin is a glycopeptide of molecular weight 1500. It is water soluble and quite stable.

Mechanisms of Action & Basis of Resistance

Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide(Figure 43–5). This inhibits the transglycosylase, preventing fur-ther elongation of peptidoglycan and cross-linking. The peptido-glycan is thus weakened, and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect.

Resistance to vancomycin in enterococci is due to modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D-lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus strains (MIC ≥ 16 mcg/mL), which have acquired the enterococ-cal resistance determinants. The underlying mechanism for reduced vancomycin susceptibility in vancomycin-intermediate strains (MICs = 4–8 mcg/mL) of S aureus is not fully known. However these strains have altered cell wall metabolism that results in a thickened cell wall with increased numbers of D-Ala-D-Ala residues, which serve as dead-end binding sites for vanco-mycin. Vancomycin is sequestered within the cell wall by these false targets and may be unable to reach its site of action.

Antibacterial Activity

Vancomycin is bactericidal for gram-positive bacteria in concentra-tions of 0.5–10 mcg/mL. Most pathogenic staphylococci, includ-ing those producing β lactamase and those resistant to nafcillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin kills staphylococci relatively slowly and only if cells are actively dividing; the rate is less than that of the penicillins both in vitro and in vivo. Vancomycin is synergistic in vitro with gentamicin and streptomy-cin against Enterococcus faecium and Enterococcus faecalis strains that do not exhibit high levels of aminoglycoside resistance.

Pharmacokinetics

Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated colitis caused by C difficile. Parenteral doses must be administered intravenously. A 1-hour intravenous infusion of 1 g produces blood levels of 15–30 mcg/mL for 1–2 hours. The drug is widely distributed in the body. Cerebrospinal fluid levels 7–30% of simultaneous serum concentrations are achieved if there is menin-geal inflammation. Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, strik-ing accumulation may occur (Table 43–2). In functionally anephric patients, the half-life of vancomycin is 6–10 days. A significant amount (roughly 50%) of vancomycin is removed during a standard hemodialysis run when a modern, high-flux membrane is used.

Clinical Uses

Important indications for parenteral vancomycin are bloodstream infections and endocarditis caused by methicillin-resistant staphy-lococci. However, vancomycin is not as effective as an antistaphy-lococcal penicillin for treatment of serious infections such as endocarditis caused by methicillin-susceptible strains. Vancomycin in combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy. Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a penicillin-resis-tant strain of pneumococcus (ie, penicillin MIC > 1 mcg/mL). The recommended dosage in a patient with normal renal function is 30–60 mg/kg/d in two or three divided doses. The traditional dosing regimen in adults with normal renal function is 1 g every 12 hours (∼ 30 mg/kg/d); however, this dose will not typically achieve the trough concentrations (15–20 mcg/mL) recom-mended for serious infections. For serious infections , a starting dose of 45–60 mg/kg/d should be given with titration of the dose to achieve trough levels of 15–20 mcg/mL. The dosage in children is 40 mg/kg/d in three or four divided doses. Clearance of vancomycin is directly proportional to creatinine clearance, and the dosage is reduced accordingly in patients with renal insuffi-ciency. For functionally anephric adult patients, a 1-g dose admin-istered once a week may be sufficient. For patients receiving hemodialysis, a common dosing regimen is a 1-g loading dose fol-lowed by 500 mg after each dialysis session. Patients receiving a prolonged course of therapy should have serum concentrations checked. Recommended trough concentrations are 10–15 mcg/mL for mild to moderate infections such as cellulitis and 15–20 mcg/mL for more serious infections such as endocarditis, meningitis, and necrotizing pneumonia.

Oral vancomycin, 0.125–0.25 g every 6 hours, is used to treat antibiotic-associated colitis caused by C difficile. Because of the emergence of vancomycin-resistant enterococci and the potential selective pressure of oral vancomycin for these resistant organisms, metronidazole had been preferred as initial therapy over the last two decades. However, receipt of oral vancomycin does not appear to be a significant risk factor for acquisition of vancomycin-resistant enterococci. Additionally, recent clinical data suggest that vancomycin is associated with a better clinical response than metronidazole for more severe cases of C difficile colitis. Therefore, oral vancomycin may be used as a first line treatment for severe cases or for cases that fail to respond to metronidazole.

Adverse Reactions

Adverse reactions are encountered in about 10% of cases. Most reactions are minor. Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. Chills and fever may occur. Ototoxicity is rare and nephrotoxicity uncommon with current preparations. However, administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 mcg/mL. Among the more common reactions is the so-called “red man” or “red neck” syndrome. This infusion-related flushing is caused by release of histamine. It can be largely prevented by prolonging the infusion period to 1–2 hours or pretreatment with an antihistamine such as diphenhydramine.

TEICOPLANIN

Teicoplanin is a glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum. Unlike vancomycin, it can be given intramuscularly as well as intravenously. Teicoplanin has a long half-life (45–70 hours), per-mitting once-daily dosing. This drug is available in Europe but has not been approved for use in the United States.

TELAVANCIN

Telavancin is a semisynthetic lipoglycopeptide derived from vancomycin. Telavancin is active versus gram-positive bacteria, including strains with reduced susceptibility to vancomycin. Telavancin has two mechanisms of action. Like vancomycin, tela-vancin inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan in the growing cell wall. In addition, it disrupts the bacterial cell membrane potential and increases mem-brane permeability. The half-life of telavancin is approximately 8 hours, which supports once-daily intravenous dosing. Telavancin is approved for treatment of complicated skin and soft tissue infec-tions at a dose of 10 mg/kg IV daily. Unlike vancomycin therapy, monitoring of serum telavancin levels is not required. Telavancin is potentially teratogenic, so administration to pregnant women must be avoided.

DALBAVANCIN

Dalbavancin is a semisynthetic lipoglycopeptide derived from teicoplanin. Dalbavancin shares the same mechanism of action as vancomycin and teicoplanin but has improved activity against many gram-positive bacteria including methicillin-resistant and vancomycin-intermediate S aureus. It is not active against most strains of vancomycin-resistant enterococci. Dalbavancin has an extremely long half-life of 6–11 days, which allows for once-weekly intravenous administration. Development of dalbavancin has been put on hold pending additional clinical trials.