Glycopeptides/Membrane-Active Antibiotics

Question 1

Vancomycin

Answer 1

• Glycopeptide antibiotic
• Active against Gram “+” bacteria, particularly staph
• Effective against multiple drug-resistant strains like MRSA, MRSE, some enterococci
• Used to treat sepsis and endocarditis caused by resistant strains
• Slow acting
• Synergistic action with aminoglycosides, treats enterococcal endocarditis

Question 2

Vanco MoA/PK

Answer 2

MoA: binds to D-Ala-D-Ala dterminus of the pentapeptide component of a growing bacterial cell wall

PK

• Poorly absorbed orally, usually IV
• Efficacy: Time-dependent
• Renally excreted unchanged, dose adjust for renal insufficiency

Question 3

Vanco AE

Answer 3

• Fever, chills, phlebitis at injection site
• Flushing (Red Man Syndrome) and shock from histamine release SLOW INFUSION
• Neutropenia, thrombocytopenia
• Ototoxicity and nephrotoxicity at certain doses with aminoglycosides
• May cause embryo/fetal toxicity in pregnancy

Question 4

VISA

Answer 4

• Vanco intermediate S. aureus

- Thickened cell wall

Question 5

VRSA

Answer 5

• Vanco resistant S. aureus
• vanA gene
• D-ala-D-lactate on terminus

Question 6

Vibativ

Answer 6

• Telavancin
• Lipoglycopeptide derivative on Vanco
• Indications: cSSSIs, HABP/VABP
• Daily dosing
• Active against VISA

Question 7

Vibativ MoA/PK

Answer 7

MoA: inhibits cell wall crosslinking (D-ala-D-ala) AND disrupts bacterial membrane potential and permeability (lipid side chain) which inhibits other cell functions from depolarization

PK

• Excreted by kidneys (dose adjust)
• Inhibits CYP3A4 and CYP3A5
• Efficacy: Concentration-dependent

Question 8

Vibativ AE

Answer 8

• Red-man syndrome
• Box Warning: nephrotoxicity, fetal risk
• QTc prolongation

Question 9

Dalvance

Answer 9

• Dalbavancin
• Lipoglycopeptide
• Indications: ABSSSI
• Active against VISA
• IV, one a week dosing

Question 10

Dalvance MoA/PK

Answer 10

MoA: Binds D-Ala-D-Ala to prevent cell wall crosslinking, dimerizes and anchors in cell membrane

PK

• Half life: 346 hours
• Efficacy: concentration dependent

Question 11

Orbactiv

Answer 11

• Oritavancin
• Lipoglycopeptide
• Indication: ABSSSI
• Active against VISA and VRSA
• 1 IV dose over 3 hours

Question 12

Orbactiv MoA/PK

Answer 12

MoA: inhibits transglycosylation and transpeptidation AND disrupts bacterial membrane, inhibits cell functions and leads to cell death

PK

• Half life: 245 hours
• Efficacy: concentration-dependent activity

Question 13

Cubicin

Answer 13

• Daptomycin
• Cell-membrane targeted agent
• Gram “+” coverage as well as active against vanco-resistant stains of staph and enterococci
• More rapidly bactericidal in vitro compared to vanco

Question 14

Cubicin MoA

Answer 14

Calcium dependent membrane depolarization leading to arrest of DNA/RNA/protein synthesis => cell death (no lysis)

Question 15

Major Mechanisms of Cubicin Resistance

Answer 15

1. Increased surface charge repulses DAP/Ca+2 complex

2. Changes in membrane composition reduces fluidity, DAP binding and efficacy (decreased phosphatidylglycerol)

Question 16

Cubicin Interations/PK

Answer 16

• Pulmonary surfactant antagonizes daptomycin, DONT USE FOR PNEUMONIA
• HMG-CoA inhibitors can enhance AE
• Efficacy: concentration dependent bactericidal action

Question 17

Cubicin AE/Monitoring

Answer 17

• AE: severe myalgias, CPK elevation

- Monitoring: weekly CPK levels (5x increase w/ symptoms or 10x increase w/o = D/C)

Question 18

Polymyxin

Answer 18

MoA: bind LPS and disrupt Gram “-“ membranes

• Polymyxin B: solubilize membrane, neurotoxic, nephrotoxic
• Colistin (Polymyxin E): solubilize membrane, nephrotoxic, LAST RESORT

Question 19

Bacitracin

Answer 19

• Cyclic peptide mixture

- MoA: inhibits dephosphorylation of lipid carrier of cell wall monomers and inhibits its transport