20 Protein Synthesis Inhibitors Cupo

Question 1

What is some background information of Quinupristin/Dalfopristin?

Answer 1

Synercid. Alternative to Vancomycin given increased VREF rates. Member of Streptogramin class. 30:70 mixture of Quinupristin:Dalfopristin. (Quin = Streptogramin B, Dalfo = Streptogramin A)

Question 2

What is the MOA of Quinupristin/Dalfopristin?

Answer 2

Sequential binding to separate sites on 50S ribosomal subunit, thus inhibiting protein synthesis. Dalfopristin, alters the ribosomal conformation such that the affinity for quinupristin is increased. A stable ternary complex of quinupristin-ribosome-dalfoprisin interrupts protein synthesis and causes cell death

Question 3

What is the spectrum of activity for Quinupristin/Dalfopristin?

Answer 3

Predominantly Gram (+): S. aureus (MSSA, MRSA), S. epidermidis (MSSE, MRSE), E. faecium (includes vanc-R strains; not E. faecalis), S. pneumoniae (includes Pen-R strains), S. agalactiae, S. pyogenes, Viridans streptococci. Others (in vitro - clinical experience lacking): M. catarrhalis, Neisseria, Clostridium, Peptostreptococcus

Question 4

What is the administration of Quinupristin/Dalfopristin?

Answer 4

IV only. Not FDA approved for < 16 years

Question 5

What is the PK of Quinupristin/Dalfopristin?

Answer 5

T1/2: 1.3-1.5hrs (despite this, Q8h-Q12h dosing based on t1/2 of active metabolites). < 20% eliminated in urine, 75% in feces

Question 6

What is the PD of Quinupristin/Dalfopristin?

Answer 6

Q + D = synergistic combination. Bactericidal except against E. faecium (“statis”). PAE: 6 hours (against S. aureus)

Question 7

What is resistance like against Quinupristin/Dalfopristin?

Answer 7

“erm” gene (streptogramin B). Acetylation-induced drug inactivation, efflux pumps (streptogramin A)

Question 8

What are the common ADRs associated with Quinupristin/Dalfopristin?

Answer 8

N/V/D (high). Athralgias, myalgias (may be up to 40% in debilitated pts w/ comorbidities, may require narcotic analgesics for pain control). Hyperbilirubinemia (reversible LFT increase). Infusion-site inflammation, pain, edema. Rash, thrombophlebitis

Question 9

What is Quinupristin/Dalfopristin’s place in therapy?

Answer 9

VRE. faecium bacteremia (usually Q8h, if hepatic insufficiency change to Q12h). MRSA bacteremia (alternative to vanco (esp. if intolerant to linezolid d/t bone marrow suppression), appears to also be synergistic with vanco)

Question 10

What is Linezolid (Zyvox)?

Answer 10

Oxazolidinone class of antimicrobials (“novel mechanism”). Convenience of IV, PO dosage forms. Predominant Gram (+) activity

Question 11

What is the MOA of Linezolid (Zyvox)?

Answer 11

Blocks formation of the initiation complex of the 50S and 30S subunits

Question 12

What is the spectrum of activity of Linezolid (Zyvox)?

Answer 12

Predominantly Gram (+): S. aureus (MSSA, MRSA), S. epidermidis (MSSE, MRSE), E. faecalis (includes vanco-R strains), E. faecium (includes vanco-R strains), S. pneumoniae (includes Pen-I, Pen-R strains), S. pyogenes. Others: Corynebacterium, Listeria mnocytogenes, M. catarrhalis, H. influenzae, Legionella, C. difficile, C. perfringens, Bacteroides

Question 13

What is the dosage/administration of Linezolid (Zyvox)?

Answer 13

Available as 600mg tablets, oral suspension, pre-made IVPB solution. Usual dosing - Adults: 600mg PO/IV Q12h. No adjustment needed in renal/hepatic failure

Question 14

What is the PK of Linezolid (Zyvox)?

Answer 14

F ~100%. T1/2: 4.2-5.4 hrs. Distributes well to perfused tissue sites (pleural, pancreas)

Question 15

What is the PD of Linezolid (Zyvox)?

Answer 15

Bacteriostatic against most (“cidal” against some Pneumococci). Concentration-independent killing. Resistance: 23S ribosomal RNA mutations. Minimal-moderate PAE. Best predictor of activity: Time > MIC

Question 16

What are the ADRs associated with Linezolid (Zyvox)?

Answer 16

Nausea, diarrhea. Hematologic** (thrombocytopenia, anemia. Risk increases w/ duration of Rx (2 weeks or longer). Use of B6 may decrease risk of developing hematologic toxicity. Weekly CBC monitoring while on therapy). Liver (increased LFTs). CNS (peripheral neuropathy, optic neuritis (irreversible)). Rash. Lactic acidosis

Question 17

What is a common DDI with Linezolid (Zyvox)?

Answer 17

SSRI’s + MAOI (e.g. linezolid) –> Serotonin Syndrome

Question 18

What are the clinical applications of Linezolid (Zyvox)?

Answer 18

Vanco-R enterococcal infections. MRSA infections (alternative to vanco)

Question 19

What are some patient instructions for Linezolid (Zyvox)?

Answer 19

May take without regard to meals. Complete the full course of therapy. Inform MD/PharmD if any OTC meds including vitamins and herbal products, cough and cold preps. Inform MD/PharmD if taking any antidepressants. Inform MD if black, tarry stools, unusual bleeding. Pregnancy Category C

Question 20

What should be avoided while on Linezolid (Zyvox)?

Answer 20

Aged cheese, aged meats, soy sauce, beer, red wine, sauerkraut

Question 21

What is the MOA of Daptomycin?

Answer 21

Binds to the bacterial cell membrane (calcium-dependent insertion of lipid tail). Rapidly depolarizes the cell membrane (efflux of potassium, destroys ion-concentration gradient). Cell death (multiple failures in biosystems, DNA, RNA, and protein synthesis)

Question 22

What is the spectrum of activity of Daptomycin?

Answer 22

Active against most isolates of the following both in vitro and in clinical infections. Aerobic and facultative Gram (+): Enterococcus faecalis (vanco-susceptible strains only). Staphylococcus aureus (including MRSA). Streptococcus agalactiae. Streptococcus dysgalactiae subsp. equisimilis. Streptococcus pyogenes

Question 23

What is the PK of Daptomycin?

Answer 23

F not applicable (IV only). T1/2: 8-9 hrs. High protein binding (90%), slow distribution from plasma, small Vd, all suggest limited tissue penetration for deep-seated infection. No hepatic metabolism, > 80% renal elimination

Question 24

What is the dosing/administration of Daptomycin like?

Answer 24

Daptomycin 4-6mg/kg should be administered over 30 minutes by intravenous infusion in 0.9% NaCl injectoin once every 24 hours. Dosing more frequently than QD is not recommended

Question 25

What are the dosage modifications for Daptomycin like?

Answer 25

Elimination is primarily by the kidney. Dosage modification for patients with CrCl < 30, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)

Question 26

What is the PD of Daptomycin?

Answer 26

Concentration-dependent killing. Bactericidal. PAE: 6hrs. Resistance: clinical failures in MRSA bacteremia noted; mechanism not well defined

Question 27

What is the key parameter for efficacy of Daptomycin?

Answer 27

Peak/MIC, AUC/MIC

Question 28

What are the ADRs like for Daptomycin?

Answer 28

GI (constipation/N/D). CNS (HA, insomnia, dizziness). CPK elevations. Dermatologic (rash, itching). Eosinophilic pneumonia

Question 29

What is Skeletal Myopathy with Daptomycin?

Answer 29

Patients receiving Daptomycin should be monitored for the development of muscle pain or weakness, particularly of the distal extremities (CPK levels monitored weekly). Patients who develop unexplained elevations in CPK while receiving Daptomycin should be monitored more frequently

Question 30

What is Daptomycin’s place in therapy?

Answer 30

FDA approved ONLY for the treatment of complicated skin and skin structure infections caused by susceptible organisms (e.g. MRSA) and bloodstream infections caused by S. aureus. Other indications include osteomyelitis

Question 31

Review of therapy, what is Linezolids place in therapy?

Answer 31

MRSA - alternative to vanco if intolerance, clinical failures (vanco heteroresistance). VRE

Question 32

Review of therapy, what is Quinupristin-Dalfopristins place in therapy?

Answer 32

MRSA - alternative to vanco if clinical failure or intolerance to linezolid. Synergy with vanco; combination therapy for recalcitrant infections

Question 33

Review of therapy, what is Daptomycin’s place in therapy?

Answer 33

For MRSA, alternative after vanco, linezolid. NOT indicated for pneumonia