Erdman - Vanc and Other Gram + Flashcards
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
glycopeptide
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.
- cross-linking
- bactericidal
- time
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
- D-alanyl-D-alanine
- thickening
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
positive
- PRSP
- bacteriostatic
- MSSA, MRSA
- C. diff
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)
variability
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)
- negligible
- IV
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
- adipose
- variable
- ONE
- obese
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
- increases
- 7-14
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
- nephrotoxicity
- after
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
3000 mg
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)
- MRSA
- PRSP
- C. diff
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)
- rate
- 1, 90, 120
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)
- VRE
- 50S, protein
- bacteriostatic
STREPTOGRAMINS Mechanisms of Resistance
alteration of ribosomal binding site (most
common – encoded by ___ gene); enzymatic inactivation
- erm
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
- PRSP
- facium, VRE, faecalis
- MRSA, MSSA
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
- time
- PAE
- IV
- minimal
- unnecessary
- suggested
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
- vancomycin
- linzolid
- daptomycin
- VRE
STREPTOGRAMINS
Drug Interactions - Cytochrome P450 ___ inhibitor
may increase serum concentrations of
- Lipid-lowering agents - HMG-CoA reductase inhibitors ( __ )
- Immunosuppressive agents – cyclosporine, ___
- Other – ___ , quinidine, lidocaine
3A4
- statins
- tacrolimus
- carbamazepine
STREPTOGRAMIN AE
- ____ irritation – significantly greater than comparators (66% vs. 33%); especially with peripheral administration
- Gastrointestinal – nausea, vomiting, diarrhea
- ___ and ___ – 2%
- Rash – 2.5%
- venous
- myalgias, arthralgias
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)
- 50S
- 70S
- protein
OXAZOLIDINONES
___ (Zyvox) and ___ (Sivextro)
- linezolid
- tedizolid
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
ribosomal
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)
- PRSP
- faecium, faecalis, VRE
- MRSA, MSSA, VISA, VRSA
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
- PAE
- rapidly, 100%
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
- VRE
- MRSA
Oxazolidinones Drug Interactions
weak inhibitors of ____ potential for drug interactions
- risk of ___ syndrome in patients receiving concomitant serotonergic agents (SSRIs)
- monoamine oxidase
- serotonin
Oxazolidinones AE
- GI
- CNS: headache, peripheral and optic neuropathy
- ___ and anemia
Thrombocytopenia
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
- concentration, bacteriocidal
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
- rarely
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
- PRSP
- faecium, faecalis, VRE
- MRSA, MSSA, VISA, VRSA, LRSA
LIPOPEPTIDES
- Rapid, ___ -dependent ___ activity
- dosage adjustments of daptomycin are required
in the presence of ___ insufficiency
- concentration, bacteriocidal
- renal
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
- vancomycin, linezolid
- VRE
- pneumonia, pulmonary
LIPOPEPTIDES
Drug Interactions
- HMG-CoA reductase inhibitors ( ___ ) – may lead to increased incidence of ___
- statins
- myopathy
LIPOPEPTIDES AE
- GI
- Headache
- injection site reactions
- rash
- ___ and ___ elevation
- acute ____ pneumonia
- myopathy, CPK
- eosinophilic
LIPOGLYCOPEPTIDES
- ___ (Vibativ)
- ___ (Dalvance)
- ___ (Orbactiv) – IV only
- telavancin
- dalbavancin
- oritavancin
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
- D-Ala-D-Ala
- membrane
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
- peptidoglycan
- vanA
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
- faecium, faecalis, VRE
- MSSA, MRSA, VISA, VRSA
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
- concentration
- bacteriocidal
- poor
- hemodyalysis
- NO
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
- adults
- vancomycin, inezolid/tedizolid, daptomycin
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)
weak
coag
LIPOGLYCOPEPTIDES AE
- Infusion-related reactions (Red Man Syndrome, all)
- ___ - telavancin
- QTc prolongation - ___
- taste disturbances - ___
- N/V/D
- foamy urine
- macrophage dysfunction
- nephrotoxicity
- telavancin
- telavancin
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.
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
