Glycopeptides

Mark Johnson, Pharm.D., BCPSAssociate Professor and Director of

Postgraduate Education

Vancomycin—A glycopeptide

http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1399

Vancomycin

• Mechanism of action– Inhibits cell wall synthesis by binding to the D-Ala-D-Ala

terminus of of peptidoglycan pentapeptide, which as a result inhibits transglycosylase, preventing peptidoglycan elongation and cross-linking

• Mechanism of Resistance: modification of D-Ala-D-Ala binding site (D-Ala is replaced by D-lactate), and thus vancomycin cannot bind to its target site

Vancomycin• Spectrum of Activity– Gram + organisms only (Staph and Strep); particularly

Staphylococci (MRSA), penicillin-resistant Streptococcus pneumoniae

– Synergistic in vitro with gentamicin and streptomycin against Enterococcus faecium and Enterococcus faecalis

– Increased incidence of VRE, but otherwise good coverage against enterococcus

– Vancomycin Resistance: VISA (GISA), VRSA– Kills Staph slowly compared to beta-lactams– Bacteriocidal

Vancomycin• Clinical Use– PO for C. difficile colitis – IV for everything else (usually serious infections including

bacteremia, endocarditis, meningitis)– Also an alternative for PCN allergic patients

Vancomycin

• Pharmacokinetics– Poorly absorbed from GI tract– Widely distributed with Vd 0.4-1L/kg; CSF levels 7-

30% of serum levels with meningeal inflammation; lung tissue 5-41% of serum levels

– Þ-distribution phase 30min; ß-elimination half-life 6-12h

– 90% excreted by glomerular filtration

Vancomycin• Adverse Effects: – Nephrotoxicity (uncommon, but ? Increasing incidence)

and Ototoxicity (rare--possibly related to very high trough conc)• More common with older preparation (“Mississippi

mud”)• Toxicity may be increased with other nephro/oto-toxic

drugs

Vancomycin• Adverse Effects: – “Red man” or “red neck” syndrome • Infusion-related flushing reaction caused by release of

histamine• Prevented by increasing the infusion time

– Phlebitis – Rash– Chills– Fever

Vancomycin

• Dosing– 15-20mg/kg (as actual body weight) every 8-

12h for most patients with normal renal function when MIC < 1

– Dose modify interval depending on renal impairment

– In seriously ill, LD 25-30mg/kg can be used to facilitate rapid attainment of target trough

– Goal AUC:MIC >400 overall; not achievable if MIC > 2 with conventional dosing

AJHP 2009;66:82-98

Vancomycin

• Monitoring: – Troughs most accurate and practical for

monitoring efficacy– Trough historically 5-10mcg/ml, now

>10mcg/mL because of MIC creep– Complicated infections (endocarditis,

osteomyelitis, meningitis, HAP caused by Staph aureus): trough 15-20mg/L

– Scr periodically

AJHP 2009;66:82-98

Vancomycin

• Dosage Forms:– Capsules (Vancocin®) 125mg and 250mg– Injection • Premixed: 500mg (100ml); 1g (200ml)• Powder for reconstitution: 500mg, 1gm, 5gm, 10gm

Telavancin (Vibativ™)Theravance

• Lipoglycopeptide antibiotic (synthetic derivative of vancomycin) for the treatment of complicated gram-positive skin infections

• MOA: inhibits bacterial cell wall synthesis and disrupts bacterial cell membrane function

Televancin vs. Vancomycin

Telavancin (Vibativ™)Theravance

• Antimicrobial Activity:– MSSA, MRSA– Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus

pneumoniae (incl. penicillin resistant), Streptococcus angiosus group– Enterococcus faecalis– Not VRE, not VRSA, maybe GISA– PAE of up to 6 hours

• Efficacy:– Skin and Skin Structure: comparable to

vancomycin and anti-staphylococcal penicillins– HAP: comparable to vancomycin

Telavancin (Vibativ™)Theravance

• ADR’s:– >10%: taste disturbance, n&v, foamy urine– Renal dysfunction: 3% (vs. 1% vancomycin) (monitor renal

function before/during therapy)– Possible: QTc prolongation, Red-man syndrome– Pregnancy C: reduced fetal weights, digit/limb deformities in

animals (need to do pregnancy test)• Drug Interactions:

– Is a CYP3A4 inhibitor, so potential exists– Can interfere with PT, INR, aPTT, ACT, factor Xa as binds to

artificial phospholipid surface—collect samples when telavancin is at trough

Telavancin (Vibativ™)Theravance

• Dosing:– 10mg/kg Q24h IV over 60min

• CrCl 30-50ml/min: 7.5mg/kg Q24h• CrCl 10-29ml/min: 10mg/kg Q48h• CrCl < 10ml/min: insufficient data• Severe hepatic impairment: unknown

– No level monitoring• Cost:– 750mg vial: $150– 250mg vial: $50