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Glycopeptides

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Vancomycin

Teicoplanin

Mode of action

  • bind to the D-ALA-D-ALA terminal end of peptidoglycan precursors. (Peptidoglycans are the basic building blocks of bacterial cell walls).
  • this inhibits the action of transglycosidase and transpeptidases (required for cross-linking of peptidoglycans - basic building block of cell wall)
  • inhibit RNA synthesis

Resistance

  • due to substitution of D-lactic acid instead of terminal D-ALA. Prevents binding of glycopeptide.

Pharmacodynamics

  • very slow killing
  • time-dependent killing
  • moderate post-antibiotic effect (approximately 2 h)
  • synergistic effect in vitro with aminoglycosides: facilitates penetration of latter into bacterial cells.

Spectrum of activity

Gram positive organisms only

Usually sensitive organisms:

Usually resistant organisms:

  • Leuconostoc spp.
  • Lactobacillus spp.
  • Pediococcus spp.
  • Erysipelothrix spp.

Glycopeptide resistant organisms

  • vancomycin and teicoplanin resistant enterococci. Several different types of resistance:
    • VanA
      • high-level resistance (MIC at least 64 mg/L)
      • r
      • t
      • r
      • results in substitution of lactate for D-Ala in terminal D-Ala-D-Ala of peptide chain in peptidoglycans and interference with glycopeptide binding
    • VanB
      • low level resistance (MIC 8-32 mg/L)
      • only inducible by vancomycin and thus does not result in teicoplanin resistance
      • also results in substitution of lactate for D-Ala
    • VanC
      • constitutive form of resistance seen in Enterococcus gallinarum
      • low level resistance
    • VanD
      • constitutive resistance found in one strain of Enterococcus faecium
      • high level resistance to vancomycin and low level resistance to teicoplanin

Vancomycin

Pharmacokinetics

Administration

Intravenous. Although can be given orally for Clostridium difficile related diarrhoea. (Note the IV preparation can be given enterally instead of the more expensive enteral preparation). Significant amounts may be absorbed from the GI tract in patients with colitis

Distribution

  • most body tissues and fluids but unless meninges are inflammed there is little diffusion into CSF
  • 55% bound to plasma protein

Elimination

  • mainly by glomerular filtration. 80% of a dose excreted within 24h in urine
  • small amount excreted in faeces
  • limited elimination by haemofiltration

Dosage

Reduce dose in renal failure and severe hepatic failure

Concentration monitoring

Aim for peak concentration approximately 30mg/l (20-40) and trough concentration <10 mg/l

Adverse effects

  • histamine release due to too rapid an infusion. Results in anaphylactoid reaction, muscular spasms, and sometimes hypotension ("red man syndrome")
  • nephrotoxicity especially in combination with other renal insults
  • very occasional ototoxicity

Teicoplanin

Pharmacokinetics

  • admin: IV/IM. Absorption after IM injection equivalent to that after IV injection

  • distribution: poor CSF penetration. Volume of distribution 0.8-1.6 l/kg

  • elimination: almost entirely renal. t1/2 155-168 hrs. Clearance values correlate with creatinine clearance. Not removed from circulation by haemodialysis

Clinical uses

  • treatment of gram positive infections

  • empirical therapy in immunocompromised patients with haematological malignancies requiring intensive chemotherapy. Associated with a lower incidence of Candida superinfection

  • as effective as vancomycin in treatment of Clostridium difficile associated diarrhoea and colitis

Adverse effects

  • one or more in approx 10% of patients

  • incidence of renal impairment (especially in combination with an aminoglycoside) lower than that associated with vancomycin

  • lesser propensity to cause anaphylactic-type reactions (“red man syndrome”)

  • allergic type reactions in 2.6%

  • altered LFTs in 1.7%

  • altered renal function tests in 0.6%

  • pyrexia 0.8%

  • ototoxicity 0.3%

Dosage

Adults with normal renal function: loading dose of 400 mg (approx 6 mg/kg) followed by 200-400 mg od. Increase maintenance dose to 12 mg/kg for patients with septic arthritis and for empirical treatment of patients with fever and neutropaenia give 3 12 hrly loading doses of 6-12 mg/kg followed by normal maintenance doses

Adults with acute or chronic renal impairment: Give usual adult dose for first few days then modify dose to maintain a trough serum level of <10 mg/l. Serum concentration monitoring also necessary in patients with a history of IV drug abuse to ensure adequate therapeutic levels.

Children < 12 years: 3 doses of 10 mg/kg 12 hrly followed by 6-10 mg/kg daily

Further reading

Brogden RN, Peters DH. Teicoplanin. A reappraisal of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy. Drugs, 1994; 47:823-54

Rahman H, Smith L. Glycopeptides. In Armstrong D, Cohen J. Infectious diseases. Mosby, London, 1999, pp7/10.1-7/10.6

Van Bambeke F. Mechanisms of action. In Armstrong D, Cohen J. Infectious diseases. Mosby, London, 1999, pp7/1.1-7/1.14


©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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