Lecture 24 oxazolidinones, daptomycin, lefamulin, chloramphenicol Flashcards
What type of class is linezolid in and what is the MOA?
is a oxazolidinone
MOA: binds to 50S ribosome near 30S ribosome interface preventing 70S initiation complex
blocks initiation of protein synthesis
competitively inhibited by chloramphenicol and clindamycin
is bacteriostatic/bactericidal
What are ways bacteria can be resistant to linezolid?
mutation to oxazolidinone binding site on 23S ribosome
other binding site mods
non-mutation related resistance ⇒ methylation
efflux
Spectrum of activity of linezolid?
Gram +: MSSA, MRSA, S. epidermidis, VISA/GISA, penicillin and ceftriaxone resistant pneumococci, E. faecalis and E. faecium including VRE, S. pyogenes, GBS, L. monocytogenes, Clostridia, peptostreptococcus,, Gram -: M. catarrhalis, H. influenzae (inconsistent)
Other: M. tuberculosis (and other mycobacteria)
What is the PK of linezolid?
available IV and PO
100% bioavailability and rapidly absorbed
elimination primarily non-renal
some experts will reduce dose after 72 hours if CrCl < 30 and anticipated tx duration to exceed 10 days
t1/2 of 4.9 hours (BID dosing)
What is the PK of tedizolid?
available IV and PO, is a prodrug
91% bioavailable
elimination primarily non-renal (no adjustment in renal failure)
t1/2 around 12 hours (QD dosing)
Linezolid and tedizolid AEs?
N/D (5%), discoloured tongue, teeth
taste altered
thrush
H/A
blood dyscrasias - thrombocytopenia, leukopenia, pure red cell aplasia
rash, allergy
5HT Syndrome: is weak competitive reversible inhibitor of MOA, may cause HTN, agitation, confusion, hyperreflexia etc when admin with ⇒ adrenergic or 5HT agents, 5HT reuptake inhibitors, tyramine (don’t need to limit it in diet)
Neuropathy and Lactic Acidosis: peripheral may start with dysesthesias in hands (poorly reversible)
optic causes gradual onset of blurring ⇒ can lead to permanent loss if not discontinued, generally reversible when detected and discontinued
What is the MOA of daptomycin?
lipophilic decanoyl side chain irreversibly binds to bacterial cell membrane
binding leads to distortions of cell membrane and thereby altered cell morphology and recruitment of proteins essential for cell division, leads to loss of ions (ex. K+) that eventually causes cell death
rapidly bactericidal (< 60 mins)
Spectrum of activity of daptomycin?
Gram +: S. aureus (MRSA), S. epidermidis, S. pneumoniae, E. faecalis, E. faecalis
What is the PK of daptomycin?
not absorbed orally, only available IV
highly protein bound and cross cells poorly
Vd: 0.091 L/Kg
excreted primarily unchanged in urine
dosed Q24H ⇒ increased to Q48H if CrCl < 30,, inactivated by pulmonary surfactant
What are the AEs of daptomycin?
increased serum CPK and rhabdomyolysis - monitor CPK, temporarily d/c statins
N/C/V, H/A
paresthesia, dysesthesia
acute eosinophilic pneumonia has been reported
What is the MOA of lefamulin?
novel systemic pleuromutilin antibacterial
inhibits bacterial proteins synthesis by interaction with 23S rRNA of 50S ribosomal subunit
What is the PK and AE of lefamulin?
available IV and PO (dosed Q12H), 25% bioavailability (slightly decreased with food)
PO dose is 4x the IV dose
primarily metabolized by 3A4, excreted mostly in feces (5-15% in urine), no adjustments for renal failure
AE: N/D/V, hypokalemia, increased liver enzymes
Spectrum of activity of lefamulin?
Gram +: staphylococci (including MRSA), streptococci
Gram -: M. catarrhalis, H. influenzae, Legionella
Other: C. pneumoniae, M. pneumoniae
What is the MOA of chloramphenicol, and how do bacteria render resistance?
actively transported into cell ⇒ binds to 50S subunit of 70S ribosome and prevents bind of tRNA
inhibits protein synthesis (bacteriostatic against many organisms)
resistance via cell impermeability and enzyme production (acetylation)
Spectrum of activity of chloramphenicol?
Gram +: S. aureus, S. epidermidis (beta-lactamase producing, not MRSA), S. pyogenes, S. pneumoniae, S. viridans, GBS, L. monocytogenes, C. diphtheria
Gram -: H. influenzae, M. catarrhalis, E. coli, enterobacter, Klebsiella, Proteus, Serratia, Citrobacter, Providencia, N. meningitidis, N. gonorrhoeae, Salmonella, Shigella, Y. enterocolitica, Y. pestis
Anaerobes: most susceptible, particularly B. fragilis
Other: mycoplasma, chlamydiae, T. pallidum, Rickettsia, leptospira
What is the PK of chloramphenicol?
absorbed well orally in adults, unpredictable in kids
IM well tolerated with peak similar to IV
diffuses well into many tissues
metabolized primarily by liver into inactive glucuronide excreted by kidneys
with children requiring decreased dose due to reduced cap for glucuronidation
t1/2 4.1 hours inadults
Monitoring: peaks <25 mcg/mL 0.5-1.5 hours post dose
> 25 can lead to bone marrow depression, 50-100 ⇒ Gray syndrome
What are AEs of chloramphenicol?
Bone Marrow Depression: dose related and reversible
reticulocytopenia, anemia, leukopenia, thrombocytopenia
risk with adult > 4 g/day, serum >25
Idiosyncratic aplastic anemia (rare): 1/24,500-40,800
may occur weeks to months after tx, mech unknown, may require bone marrow transplant
Gray Baby Syndrome: in neonates - ab distension, vomiting, flaccidity, cyanosis, circulatory collapse, death
may present with unexplained metabolic acidosis
associated with levels > 50 mcg/mL, limit dose in neonates to 25 mg/kg/day
Optic Neuritis: with prolonged tx
Other: rash, drug fever, anaphylaxis, Herxheimer rxn *syphilis, brucella, typhoid), interference with Vit K synthesis
What are some noted drug intx for chloramphenicol?
it inhibits 2C9, 3A4 and others, may prolong t1/2 of ⇒ tolbutamide, chlorpropamide, phenytoin, cyclophosphamide, warfarin
