Antibacterial Pharmacology II: Cell Envelope Disruptors: Glycopeptides & Lipoglycopeptides, Lipopeptides

Glycopeptide antibiotics

vancomycin PO/IV/others

Glycopeptides MOA

- Inhibit cell wall synthesis by binding the D-ala-D-ala subunit of peptidoglycan precursors

- AUC/MIC-dependent, bactericidal

Vancomycin spectrum of coverage for gram (+)

- Staphylococcus spp.

- Streptococcus spp.

- Enterococcus spp.

- effective against MRSA***

- Beta-lactams are more effective than vancomycin for MSSA bloodstream infections

T/F: Vancomycin is more effective than other beta-lactams for bloodstream MSSA infections

FALSE

Glycopeptides: Vancomycin Clinical Use

- IV: moderate-severe MRSA infections

- PO/rectal: C. diff infections

Glycopeptides: Vancomycin renal

- renal adjustments REQUIRED

- significantly prolong t1/2 w/ renal impairment

CNS penetration of vancomycin

limited CNS penetration, but increases w/ inflamed meninges, long history of use in CNS

Vancomycin ADRs

- infusion-related reactions, Red Man Syndrome

- nephrotoxicity

- AKI

Vancomycin monitoring

therapeutic drug monitoring (TDM)

Vancomycin resistance

- VRE (vancomycin-resistant Enterococcus)

- VanA gene

Vancomycin clinical considerations

- IV is drug of choice for moderate-severe MRSA infections

- PO used for C. diff infections

- Consider alternatives if high MIC (>=2), treatment failure, severe kidney damage due to vancomycin therapy

Vancomycin Infusion Reaction "Red Man Syndrome"

- ADR, but NOT an allergy

- it is, however d/t a histamine-release syndrome

- slow down infusion to PREVENT, no greater than 1 g/hr

- to MANAGE, slow down infusion to no faster than 1 g over 100 minutes

- to manage, can use antihistamines

Lipoglycopeptides

- dalbavanacin IV

- oritavanacin IV

- telavancin IV

Lipoglycopeptides gram (+)

- Staphylococcus spp.

- Streptococcus spp.

- Enterococcus spp.

- treats MRSA

Lipoglycopeptides Clinical Use

- moderate-severe gram-positive infections, mainly MRSA

- most commonly acute bacterial skin and skin structure infections (ABSSSIs)

Lipoglycopeptides CNS penetration

generally poor CNS/CSF penetration

Lipoglycopeptides dose adjustments

- dalbavancin and telavancin REQUIRE renal adjustments

- oritavancin does NOT require renal adjustment

Lipoglycopeptides telavancin BBW

embryofetal toxicity, nephrotoxicity, moderate-severe renal impairment, increased mortality in HAP/VAO

Lipoglycopeptides resistance

• VRE (vancomycin-resistant Enterococcus) (ortiavancin retains activity)

• VanA gene

Lipoglycopeptides Clinical Considerations

• Very long half-lives → infrequent dosing (outside of telavancin)

• Primarily used for SSTIs

- dalbavancin and oritavancin are great options for outpatient therapy/avoiding hospitalization

• Telavancin has more toxicity → not commonly used

T/F: Both glycopeptides (vancomycin) and lipoglycopeptides have MSSA AND MRSA coverage

TRUE

Which lipoglycopeptide does NOT have a renal adjustment

oritavanacin

Lipopetides agent

daptomycin IV

Lipopetides: Daptomycin MOA

- disrupts the bacterial cell membrane (via calcium-dependent insertion of its lipid tail)

- Cmax:MIC-dependent, bactericidal

Daptomycin spectrum of coverage for gram (+)

- Staphylococcus spp.

- Streptococcus spp.

- Enterococcus spp.

- effective for MRSA

- has coverage against VRE*

- Gram(+) ONLY

Daptomycin clinical use

- moderate-severe gram-positive infections, mainly MRSA and VRE

- cSSTIs, bacteremia, endocarditis

- NOT to be used for respiratory tract infections

Daptomycin administration

once daily dosing

Can daptomycin be used in pneumonia? Why or why not?

- NO!!! IT CANT BE

- it is inactivated by pulmonary surfactant

Daptomycin CNS penetration

generally poor CNS/CSF penetration

Daptomycin renal

renal adjustment REQUIRED

Daptomycin ADRs

- myopathy/rhabdomyolysis (↑ creatinine phosphokinase/CPK)

- DRESS (drug reaction eosiniphilia & systemic symptoms)

Daptomycin monitoring

- CPK levels weekly (more frequent if statins or renal impairment)

Daptomycin DDIs

Other agents that increase risk for myopathy/rhabdomyolysis ( statins)

Daptomycin clinical considerations

• Rapidly bactericidal against gram positive organisms (including MRSA, VRE)

• Usually used to treat moderate-severe MRSA infections (bacteremia, endocarditis)

• Inactivated by pulmonary surfactant → NOT for pneumonia

Overall: Glycopeptides/Lipopeptides

- gram-positive coverage only

- key agents for MRSA and resistant gram-positive infections (VRE)

- NO activity against gram-negatives

- vancomycin/lipoglycopeptides inhibit cell wall synthesis

- daptomycin disrupts the cell membrane

- daptomycin CANNOT be used for pneumonia

- Vancomycin needs drug level monitoring

- Dalbavanacin/oritavancin are long-acting agents

Cell wall inhibitors

- beta-lactams

- glycopeptides-vancomycin

- lipoglycopeptides (dalbavancin, oritavancin, telavancin)

- bacitracin

Cell membrane inhibitors

- lipopeptides - daptomycin

- polymyxins