Erdman - Vanc and Other Gram +

Question 1

CHEMISTRY

Vancomycin is derived from Streptomyces orientalis and has a unique structure in
that it is a complex tricyclic ___ with a molecular weight of 1500 Dalton

Answer 1

glycopeptide

Question 2

MOA

• Vancomycin inhibits synthesis and assembly during the second stage of cell wall synthesis by firmly binding to the D-alanyl-D-alanine portion of cell wall precursors. Vancomycin prevents ___ and further elongation of peptidoglycan
• Vancomycin is slowly ___ in a ___ -dependent (?) manner, except
  against Enterococcus spp. where it displays bacteriostatic activity.

Answer 2

• cross-linking
• bactericidal
• time

Question 3

MECHANISMS OF RESISTANCE

• In vancomycin resistant Enterococcus (VRE) and vancomycin resistant Staphylococcus aureus (VRSA), resistance to vancomycin is due to modification
  of the ___ vancomycin-binding site
• In vancomycin intermediate Staphylococcus aureus (VISA), resistance to vancomycin is due to ___ of the peptidoglycan layer of the cell wall, restricting access of vancomycin to its site of activity

Answer 3

• D-alanyl-D-alanine
• thickening

Question 4

SPECTRUM OF ACTIVITY

Vancomycin displays activity against many Gram ___ aerobic and anaerobic bacteria
- Groups A, B, C, D, F, and G streptococci
- Viridans streptococci
- Streptococcus pneumoniae (including ___ )
- Enterococcus faecalis and faecium (ONLY ___ )
- Staphylococcus aureus and coagulase-negative staphylococci (both ___ and ___ )
- Corynebacterium spp.
- Listeria monocytogenes
- Actinomyces
- Clostridium spp. (INCLUDING ___ )

Vancomycin is NOT active against Gram-negative aerobes or anaerobes

Answer 4

positive
- PRSP
- bacteriostatic
- MSSA, MRSA
- C. diff

Question 5

Vanc

Interpatient ___ exists in the pharmacokinetic characteristics of volume of distribution and clearance of vancomycin. The PD parameter associated with efficacy appears to be the AUC/MIC (target = 400 to 600)

Answer 5

variability

Question 6

Vanc

Absorption
- Absorption of vancomycin from the gastrointestinal tract is ___ after oral administration. Absorption may occur with oral administration in the presence of intense inflammatory colitis, with detectable serum concentrations occasionally observed in patients with renal insufficiency
- For the treatment of systemic infections, intermittent ___
infusion is the preferred route of administration (not IM)

Answer 6

• negligible
• IV

Question 7

Vanc

Distribution
- Vancomycin is widely distributed into body tissues and fluids, including pleural fluid, synovial fluid, ascites, ___ tissue, and bile
- Vancomycin displays ___ penetration into the CSF, even in the presence of inflamed meninges
- Vancomycin takes approximately ___ HOUR to distribute from the plasma compartment into peripheral tissues and fluids
- There is limited PK data in ___ patients

Answer 7

• adipose
• variable
• ONE
• obese

Question 8

Vanc

Elimination
In adults with normal renal function, the elimination half-life = 6 to 8 hours. The half-life progressively ___ as renal function decreases
- In patients with end-stage renal disease, the elimination half- life of vancomycin approaches __ - __ days

Answer 8

• increases
• 7-14

Question 9

There are few well-controlled clinical trials relating vancomycin serum concentrations to efficacy; however, high troughs and high AUCs may lead to ___
- Peak concentrations should be obtained one hour ___ the end of
infusion

Answer 9

• nephrotoxicity
• after

Question 10

Vanc Dosing

TBW (up to ~120 kg) should be used for dosing in obese patients ➡ maximum initial doses should not exceed 2000 mg to ___ mg

Answer 10

3000 mg

Question 11

Vanc CLINICAL USES

• Infections due to ___
• Serious Gram-positive infections in patients allergic to B-lactam antibiotics
• Infections caused by resistant Gram positive organisms such as Corynebacterium jeikeium or ___
• Perioperative prophylaxis
• ORAL vancomycin is the drug of choice for the treatment of ___ colitis (125 mg PO Q 6 hours)

Answer 11

• MRSA
• PRSP
• C. diff

Question 12

Vanc ADVERSE EFFECTS

Red-Man Syndrome (AKA Red Neck Syndrome, Infusion-Related Reaction)
- Reaction is related to the ___ of vancomycin infusion
- To minimize or prevent this reaction, vancomycin doses of 1 gram should be infused over at least ___ hour and larger doses should be infused over ___ to ___ minutes

Nephrotoxicity

Ototoxicity

Hematologic - neutropenia, thrombocytopenia, and rarely eosinophilia; especially with prolonged therapy

Other - thrombophlebitis, muscle spasms in the back and neck; cardiovascular
collapse (rapid infusion); drug fever, interstitial nephritis (rare)

Answer 12

• rate
• 1, 90, 120

Question 13

STREPTOGRAMINS

QUINUPRISTIN / DALFOPRISTIN (Synercid)
- developed in response to the need for antibiotics with activity against resistant Gram- positive organisms, especially ___
- act individually on the ___ ribosomal subunit to inhibit early and late stages of bacterial ___ synthesis; each agent alone is ___, but the combination produces an additive or synergistic effect (sometimes bactericidal)

Answer 13

• VRE
• 50S, protein
• bacteriostatic

Question 14

STREPTOGRAMINS Mechanisms of Resistance

alteration of ribosomal binding site (most
common – encoded by ___ gene); enzymatic inactivation

Answer 14

• erm

Question 15

STREPTOGRAMINS SOA

Gram positive organisms
- Group Streptococci
- Viridans Streptococci
- Streptococcus pneumoniae (including ___ )
- Enterococcus ___ ONLY – including ___ (however, NOT ACTIVE vs. E. ___ )
- ___ and ___
- Others – Listeria monocytogenes, Clostridium (not C. difficile), Peptostreptococcus

Gram negatives - limited

atypical - not used here clinically

Answer 15

• PRSP
• facium, VRE, faecalis
• MRSA, MSSA

Question 16

Pharmacology STREPTOGRAMINS

• ___ -dependent bactericidal activity (when bactericidal)
• Significant ___ exists for Gram-positive organisms
• Absorption – only available ___
• Distribution: ___ CSF penetration
• Elimination: dosage adjustments ___ in patients with renal insufficiency, but ___ in patients with hepatic insufficiency

Answer 16

• time
• PAE
• IV
• minimal
• unnecessary
• suggested

Question 17

STREPTOGRAMINS Clinical Uses

Clinical Uses and Dosing (very expensive - $1118 to $1677 per day for a 70-kg adult)
- only considered when ___ , ___ , AND ___ cannot be used
- ___ bacteremia

Answer 17

• vancomycin
• linzolid
• daptomycin
• VRE

Question 18

STREPTOGRAMINS

Drug Interactions - Cytochrome P450 ___ inhibitor

may increase serum concentrations of
- Lipid-lowering agents - HMG-CoA reductase inhibitors ( __ )
- Immunosuppressive agents – cyclosporine, ___
- Other – ___ , quinidine, lidocaine

Answer 18

3A4
- statins
- tacrolimus
- carbamazepine

Question 19

STREPTOGRAMIN AE

• ____ irritation – significantly greater than comparators (66% vs. 33%); especially with peripheral administration
• Gastrointestinal – nausea, vomiting, diarrhea
• ___ and ___ – 2%
• Rash – 2.5%

Answer 19

• venous
• myalgias, arthralgias

Question 20

OXAZOLIDINONES

Mechanism of Action – Oxazolidinones bind to the ___ ribosomal subunit near the surface interface of the 30S subunit, producing inhibition
of the ___ initiation complex (ultimately, inhibits ___ synthesis)

Answer 20

• 50S
• 70S
• protein

Question 20

OXAZOLIDINONES

___ (Zyvox) and ___ (Sivextro)

Answer 20

• linezolid
• tedizolid

Question 21

OXAZOLIDINONES MOR

alteration of the ___ subunit target site (chromosomal mutations in genes encoding 23S or ribosomal proteins) has rarely emerged during therapy of infections due to Enterococcus spp. and S. aureus
- cross resistance exists between linezolid and tedizolid

Answer 21

ribosomal

Question 22

Oxazolidinones SOA

Gram positive
- Group Streptococci
- Viridans Streptococci
- Streptococcus pneumoniae (including ___ )
- Enterococcus ___ AND ___ (including ___ )
- ___ , ___ , ___ , and ___
- Others – Listeria monocytogenes, Clostridium (not C difficile), Bacillus, Peptostreptococcus, Propionibacterium acnes

Gram-negative organisms – INACTIVE

Atypical organisms – not used
here clinically)

Answer 22

• PRSP
• faecium, faecalis, VRE
• MRSA, MSSA, VISA, VRSA

Question 23

Oxazolidinones

• Primarily bacteriostatic; T>MIC is the major predictor of efficacy for linezolid and AUC/MIC correlates with tedizolid activity
• ___ exists for Gram-positive organisms
• Absorption – linezolid is ___ and completely absorbed after oral administration with an oral bioavailability of ___ %
• Distribution: readily distribute into well-perfused tissues; limited data suggest that 30% of simultaneous linezolid serum concentrations are achieved in the CSF
• linezolid protein binding = 31%, tedizolid protein binding = 70-90%
• Elimination: neither drug requires dosage adjustment in the presence of renal insufficiency

Answer 23

• PAE
• rapidly, 100%

Question 24

# Oxazolidinones Clinical Uses and Dosing - very expensive: generic linezolid $22 (IV) to < $4 (PO) per day and tedizolid $355 (IV) to $445 (PO) per day - reserved for management of serious or complicated infections caused by resistant organisms, especially for infections where vancomycin or β-lactams cannot be used; good oral absorption provides convenient option for “stepdown” therapy - Treatment of ___ infections (bacteremia, UTI; usually the drug of choice) - Complicated skin and skin structure infections caused by MSSA, MRSA, or S. pyogenes - Linezolid 600 mg IV or PO every 12 hours or Tedizolid 200mg PO daily {for 6 days - Community-acquired pneumonia due to PSSP, PRSP, MSSA – Linezolid 600 mg IV or PO every 12 hours - Nosocomial pneumonia due to MSSA, ___ , PSSP, PRSP – Linezolid 600 mg IV or PO every 12 hours

Answer 24

- VRE - MRSA

Question 25

# Oxazolidinones Drug Interactions weak inhibitors of ____ potential for drug interactions - risk of ___ syndrome in patients receiving concomitant serotonergic agents (SSRIs)

Answer 25

- monoamine oxidase - serotonin

Question 26

# Oxazolidinones AE - GI - CNS: headache, peripheral and optic neuropathy - ___ and anemia

Answer 26

Thrombocytopenia

Question 27

# LIPOPEPTIDES Daptomycin (Cubicin) – IV only - Mechanism of Action – binds to bacterial membranes and inserts its lipophilic tail into the cell wall to form a transmembrane channel ➡ leakage of cellular contents and rapid depolarization of the membrane potential leading to inhibition of protein, DNA, and RNA synthesis, resulting in bacterial cell death - rapid, ___ -dependent ___ activity | caprisun MOA

Answer 27

- concentration, bacteriocidal

Question 28

# LIPOPEPTIDES Mechanism of Resistance – Resistance to daptomycin has been ___ reported in VRE and MRSA due to altered cell membrane binding through loss of a membrane protein

Answer 28

- rarely

Question 29

# LIPOPEPTIDES SOA Gram-positive aerobes – excellent activity - Group and viridans Streptococci - Streptococcus pneumoniae (including ___ ) - Enterococcus ___ AND ___ (including ___ – static) - ___ , ___ , ___ , ___ , and ___ - Corynebacterium jeikeium Gram-negative aerobes – INACTIVE

Answer 29

- PRSP - faecium, faecalis, VRE - MRSA, MSSA, VISA, VRSA, LRSA

Question 30

# LIPOPEPTIDES - Rapid, ___ -dependent ___ activity - **dosage adjustments of daptomycin are required in the presence of ___ insufficiency**

Answer 30

- concentration, bacteriocidal - renal

Question 31

# LIPOPEPTIDES Clinical Uses and Dosing (fairly inexpensive: $30 per 500mg vial) - reserved for treatment of serious/complicated infections caused by resistant Gram-positive bacteria where ___ and/or ___ cannot be used - Staphylococcus aureus bacteremia and endocarditis - Serious infections due to MRSA or ___ - Daptomycin should NOT be used for the treatment of ___ since the compound is inactivated by ___ surfactant

Answer 31

- vancomycin, linezolid - VRE - pneumonia, pulmonary

Question 32

# LIPOPEPTIDES Drug Interactions - HMG-CoA reductase inhibitors ( ___ ) – may lead to increased incidence of ___

Answer 32

- statins - myopathy

Question 33

# LIPOPEPTIDES AE - GI - Headache - injection site reactions - rash - ___ and ___ elevation - acute ____ pneumonia

Answer 33

- myopathy, CPK - eosinophilic

Question 34

# LIPOGLYCOPEPTIDES - ___ (Vibativ) - ___ (Dalvance) - ___ (Orbactiv) – IV only

Answer 34

- telavancin - dalbavancin - oritavancin

Question 35

# LIPOGLYCOPEPTIDES MOA interfere with the polymerization and cross-linking of peptidoglycan by binding to the ___ terminus. - The lipid side chain anchors the drugs to the cell ___ and concentrates the drug at the site of action

Answer 35

- D-Ala-D-Ala - membrane

Question 36

# LIPOGLYCOPEPTIDES MOR Alteration in the ___ terminus (in VRE) ➡ especially ___ (gene) resistance where D-Ala-D-Ala is changed to D-Ala- D-Lac affects the activity of telavancin and dalbavancin; however, oritavancin still maintains activity

Answer 36

- peptidoglycan - vanA

Question 37

# LIPOGLYCOPEPTIDES SOA Gram-positive aerobes - Group streptococci - viridans streptococci - Streptococcus pneumoniae - Enterococcus ___ AND ___ - some strains of ___ display resistance to telavancin and dalbavancin - ___ , ___ , and ___ ; oritavancin also displays activity against ___ Gram-negative aerobes – INACTIVE

Answer 37

- faecium, faecalis, VRE - MSSA, MRSA, VISA, VRSA

Question 38

# LIPOGLYCOPEPTIDES ___ -dependent ___ activity, where the AUC/MIC is the best predictor of efficacy - ___ CSF penetration - Telavancin - dosage adjustments are suggested in the presence of ___ insufficiency - Dalbavancin - dosage adjustments suggested in patients with severe renal insufficiency who are not receiving ___ - Oritavancin - ___dosage adjustments are required in renal or hepatic insufficiency

Answer 38

- concentration - bacteriocidal - poor - hemodyalysis - NO

Question 39

# LIPOGLYCOPEPTIDES Clinical Uses and Dosing - should only be considered in ___ with infections due to resistant Gram-positive organisms where ___ , ___ / ___, AND ___ cannot be used | all very expensive

Answer 39

- adults - vancomycin, inezolid/tedizolid, daptomycin

Question 40

# LIPOGLYCOPEPTIDES Drug/Lab Interactions - oritavancin is a ___ inducer of CYP3A4 and a non-selective inhibitor of CYP2C9 and CYP2C19 (no interactions noted in limited studies performed) - telavancin and oritavancin interfere with ___ tests (PT, INR, PTT)

Answer 40

weak coag

Question 41

# LIPOGLYCOPEPTIDES AE - Infusion-related reactions (Red Man Syndrome, all) - ___ - telavancin - QTc prolongation - ___ - taste disturbances - ___ - N/V/D - foamy urine - macrophage dysfunction

Answer 41

- nephrotoxicity - telavancin - telavancin

Question 42

# LIPOGLYCOPEPTIDES Use During Pregnancy - ___ is pregnancy category C - a black box warning exists warning against use during pregnancy; pregnancy test needed before use in women of childbearing potential.

Answer 42

Telavancin Dalbavancin and Oritavancin are also Pregnancy Category C due to lack of adverse developmental outcomes in animal studies and lack of safety data in human