Oxazolidinones, Daptomycin, Lefamulin, & Chloramphenicol

Question 1

Oxazolidinones
Linezolid (Zyvox)

Answer 1

 Bind to 50S ribosome near the 30S ribosome
interface preventing the 70S initiation complex
 blocks initiation of protein synthesis
 competitively inhibited by chloramphenicol and
clindamycin
 Bacteriostatic / Bactericidal
 Resistance reported
 (VRE, MRSA, S. aureus, S. epidermidis)

Question 2

Linezolid - Resistance

Answer 2

Mutation to oxazolidinone binding site on 23S ribosome*
 Other binding site modifications
 Non-mutation-related resistance - methylation (cross-resistance)
 Efflux

Question 3

Linezolid Spectrum of Activity

Answer 3

Resistant Gram-positive organisms including:
 MSSA, MRSA, S. epidermidis, VISA (GISA)
 Penicillin- & ceftriaxone-resistant pneumococci
 E. faecalis and E. faecium, including VRE
Other
 S. pyogenes, Grp B Streptococci
 Listeria monocytogenes
 M. catarrhalis, H. influenzae (inconsistent)
 Clostridia, Prevotella, Peptostreptococcus,
M. tuberculosis (and other mycobacteria)

Question 4

Linezolid Pharmacokinetics

Answer 4

 Available IV and PO
 100% bioavailability, rapidly absorbed
 elimination primarily non-renal (no dose adjustment in renal failure)
 (metabolized to two inactive metabolites excreted renally – significance in renal failure not known)
 t1/2 5.5 hr (BID dosing)

Question 5

Tedizolid (Sivextro) Pharmacokinetics

Answer 5

 Available IV and PO
 Prodrug (tedizolid phosphate) – both formulations
 ~91% bioavailable
 Elimination primarily non-renal
 (no dosage adjustment in renal failure)
 t1/2 ~ 12 hr (once daily dosing

MIC tends to be lower than linezolid
uses quite a bit lower dose, AUC/MIC is comparable

Question 6

Linezolid Adverse Effects

Answer 6

 Nausea 5.4%, diarrhea 5.2%
 discolouration of the tongue 2.5%, tooth discolouration,
taste perversion 2.3%, oral monillia 2.3%
 headache 2.3%
 optic neuropathy, peripheral neuropathy
 *Blood dyscrasias – thrombocytopenia, leukopenia,
pure red cell aplasia
 Rash, allergy
 lactic acidosis, within first week

thru protein synth inhibition in mitchondira

Question 7

Linezolid Adverse Effects

Serotonin syndrome

Answer 7

Serotonin syndrome
 Linezolid a weak competitive, reversible inhibitor of MAO
 May cause hypertension, agitation, confusion,
hyperreflexia, myoclonus, tremors, etc. when coadministered with:
 adrenergic or serotonergic agents
(e.g. phenylpropanolamine or pseudoephedrine)
 serotonin reuptake inhibitors
 tyramine - no need to limit tyramine in diet

Question 8

Linezolid Adverse Effects\

Neuropathy and Lactic Acidosis

Answer 8

 Peripheral neuropathy may begin with dysesthesias in
the hands (poorly reversible)
 Optic neuropathy causes gradual onset of blurring
 Can lead to permanent loss of useful visual acuity if not
discontinued
 Generally reversible when detected and discontinued early
 Lactic acidosis

Question 9

Linezolid Adverse Effects\

Reasons to discontinue

Answer 9

 Thrombocytopenia (2.6%)
 May occur in 47% after 10 days (immune mediated)
 Dermatological (2.5%)
 Leukopenia (0.85%)
 Allergy (0.3%)
 May also cause pure red cell aplasia
(suppression of erythropoiesis) ( if > 2 wks)

Question 10

Tedizolid Adverse Effects

Answer 10

similar to linezolid, but may occur less

frequently

Question 11

Other Oxazolidinones

Answer 11

Radezolid
 Phase II
Sutezolid
 Phase II
Cadazolid
 Phase III

Question 12

Daptomycin

Mechanism of Action

Answer 12

► Lipophilic decanoyl side chain irreversibly binds to the
bacterial cell membrane
► Binding leads to distortions of the cell membrane and thereby
altered cell morphology and recruitment of proteins essential
for cell division. Leads to loss of ions (e.g., K+) that eventually
results in cell death
► Rapidly bactericidal (< 60 minutes)

Question 13

Daptomycin Resistance

Answer 13

► Cell membrane modifications

beta lactams use with it decrease resistance, dapto may be made more susceptible

Question 14

Daptomycin – Spectrum of Activty

Answer 14

► S. aureus, MRSA
► S. epidermidis
► S. pneumoniae
► E. faecalis
► E. faecium
► Low risk of resistance
► Emergence of nonsusceptibility more frequent in enterococci

Question 15

Daptomycin Pharmacokinetics

dosage form

Answer 15

► Not absorbed orally, only available IV
► Highly protein bound and crosses cell membranes poorly
► Low Vd 0.091 L/Kg
► Excreted primarily unchanged in urine
► Dosing interval q24h
► increased to q48h if CrCl < 30 ml/min
►Inactivated by pulmonary surfactant

know you need to adjust dose

Question 16

Daptomycin Adverse Effects

Answer 16

 Increased serum CPK (~ 7%) and rhabdomyolysis (< 1%)
Creatine phosphokinase
 Monitor CPK, temporarily d/c statins
 Most frequent – constipation, nausea, vomiting, headache
(3 - 12% - similar to comparator)
 Paresthesia, dysesthethia (9.2%)
 mild – moderate, short-lived, reversible despite continued therapy
 Acute eosinophilic pneumonia associated with daptomycin use have been reported

Question 17

Lefamulin

Xenleta

Answer 17

 A novel systemic pleuromutilin
antibacterial
 Inhibits bacterial protein synthesis by
interaction with 23S rRNA of 50S
ribosomal subuni

Question 18

Lefamulin
dosage form
spectrum of act

Answer 18

 Available IV and PO (dosed q12h) – bioavailability ~ 25% (food slightly decreases)
PO dose is 4x the IV dose, so levels would be expected to be the same

 Active against many Staphylococci (including MRSA), as well as:
Streptococci,
M. catarrhalis,
H. influenzae,
Legionella,
C. pneumoniae,
M. pneumoniae
No cross-resistance with other major classes of antibacterials
atypicals, other common ones
potential for CAP empiric

Question 19

Lefamulin
metabolism
ae

Answer 19

Metabolism
 Primarily CYP 3A4
 Excreted mostly in the feces, 5-15% in urine
 No dosage adjustment required for renal impairment
Adverse Effects
 Diarrhea (12%), Nausea (3-5%), Vomiting
 Hypokalemia (3%), increased liver enzymes (<3%)