Vancomycin and Other Agents with Activity Against Gram-Positive Aerobes Flashcards
What are the glycopeptides?
vancomycin
What is the mechanism of action of vancomycin?
inhibits the synthesis of the bacterial cell wall by blocking glycopeptide polymerization at a site different from that of beta-lactams. Inhibits synthesis and assembly during the 2nd stage of cell wall synthesis by firmly binding to the D-ala-D-ala portion, preventing cross-linking and further elongation of peptidoglycan lysis. Slowest bactericidal in a time-dependent manner except it is bacteriostatic against enterococcus spp.
What are the streptogramins?
quinupristin-dalfopristin (synercid)
What is the mechanism of action of quinupristin-dalfopristin?
Developed in response to vancomycin-resistant enterococcus (VRE). Act individually on the 50S ribosomal subunit to inhibit early and late stages of bacterial protein synthesis; each agent alone is bacteriostatic, but in combo can be bactericidal.
What are the oxazolidinones?
linezolid, tedizolid
What is the mechanism of action of oxazolidinones?
developed in response to the need for antibiotics with activity against resistant gram-positive organisms, especially MRSA, VISA, and VRE. Bind to the 50S ribosomal subunit near the surface interface of the 30S subunit, producing inhibition of the 70S initiation complex for protein synthesis (inhibits protein synthesis). This MOA is unique, making cross-resistance with other protein synthesis inhibitors unlikely. Mostly bacteriostatic.
What are the lipopeptides?
daptomycin
What is the mechanism of action of daptomycin?
: 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, RNA, synthesis, resulting in bacterial cell death. Exhibits rapid concentration-dependent bactericidal activity.
What are the lipoglycopeptides?
telavancin, dalbavancin, oritavancin
What is the mechanism of action of lipoglycopeptides?
Interfere with the polymerization and cross-linking of peptidoglycan by binding to the D-Ala-D-Ala terminus. Oritavancin and telavancin also bind to bacterial membranes and insert their lipophilic tails into the cell wall to form a transmembrane channel causes leakage of cellular contents and rapid depolarization of the membrane potential leading to inhibition of protein, DNA, and RNA synthesis –> bacterial cell death.
What are the mechanisms of resistance to vancomycin?
modification of the D-ala-D-ala vancomycin binding site of the peptide side chain of peptidoglycan precursors by expression of vanA gene. Terminal D-ala replaced by D-lactate. Also from thickening of peptidoglycan layer of cell wall, restricting access of vancomycin to its site of activity.
What are the mechanisms of resistance to quinupristin-dalfopristin?
Alteration of ribosomal binding site (most common by erm gene – methylation); enzymatic inactivation.
What are the mechanisms of resistance to oxazolidinones?
alteration of ribosomal subunit target site (chromosomal mutations in genes encoding 23S or ribosomal proteins).
What are the mechanisms of resistance to daptomycin?
Rarely reported; altered cell membrane binding through loss of a membrane protein.
What are the mechanisms of resistance to lipoglycopeptides?
Alteration in peptidoglycan terminus vanA resistance where D-Ala-D-Ala is changed to D-Ala-D-Lac (oritavancin still maintains activity!).
Spectrum of activity of vancomycin
- Displays activity against many gram-positive aerobic and anaerobic bacteria: penicillin resistant streptococcus pneumoniae (PRSP), enterococcus faecalis and faecium, both MSSA and MRSA, C diff.
- NOT active against gram-negative aerobes or anaerobes.
- Oral vancomycin and metronidazole only 2 that cover C diff.
Spectrum of activity of quinupristin-dalfopristin
- Gram-positive organisms: PRSP, enterococcus faecium ONLY, including VRE, MSSA, MRSA.
- Gram-negative aerobes: NOT active against Enterobacteriaceae.
- Atypical organisms: not used here clinically.
Spectrum of activity of oxazolidinones
- Gram positive organisms: PRSP, enterococcus faecium AND faecalis (including VRE), MRSA, MSSA, VISA, VRE
- INACTIVE against gram-negative organisms.
- Not used clinically in atypical organisms.
Spectrum of activity of daptomycin
- Gram-positive aerobes: excellent activity – PRSP, enterococcus faecium AND faecalis (including VRE), staphylococcus aureus (MS, MR, VI, VR, LR).
- INACTIVE against gram-negative aerobes.
Spectrum of activity of lipoglycopeptides
- Gram-positive aerobes: excellent activity – enterococcus faecium AND faecalis (some strains of VRE display resistance to telavancin and dalbavancin); staphylococcus aureus and CNS (MS, MR, VI, oritavancin displays activity against VRSA).
- INACTIVE against gram-negative aerobes.
PK properties of vancomycin
absorption from GI tract is negligible after oral administration, for the treatment of systemic infection, intermittent IV infusion preferred (not IM). Widely distributed into body (adipose tissues) and displays variable penetration into CSF. Take ONE HOUR to distribute from plasma compartment into peripheral tissues/fluids. Half-life progressively increases as renal function decreases, needs dose adjustment in renal insufficiency and is removed during dialysis.
1. Serum concentration monitoring – high troughs/AUCs may lead to nephrotoxicity; peak concentration should be obtained one hour after end of infusion; target AUC = 400-600.
PK properties of quinupristin-dalfopristin
significant PAE for gram-positive organisms. Minimal penetration into CSF. Both eliminated by hepatic clearance or biliary elimination – NO dosage adjustments in patients with renal insufficiency, but suggested in patients with hepatic insufficiency.
PK properties of oxazolidinones
: PAE exists for gram-positive organisms. Linezolid rapidly and completely absorbed after oral administration with oral bioavailability of 100%. Limited penetration into CSF. Eliminated by both renal and non-renal routes and do NOT require dosage adjustment in presence of renal insufficiency.
PK properties of daptomycin
rapid, concentration-dependent bactericidal activity; highly protein bound to serum albumin; dosage adjustment required in renal insufficiency.
PK properties of lipoglycopeptides
concentration dependent bactericidal activity (AUC/MIC). Poor CSF penetration, 90% protein bound. None removed by HD. Telavancin and dalbavancin require dosage adjustments with renal insufficiency, but oritavancin does not.
Clinical uses of vancomycin
THE drug of choice for MRSA and C diff. colitis (oral)! Serious gram-positive infections in patients allergic to beta-lactam antibiotics; penicillin resistant streptococcus pneumoniae (PRSP).
Clinical uses of quinupristin-dalfopristin
only considered when vancomycin, linezolid, and daptomycin cannot be used because it’s very expensive – enterococcus faecium (VRE) bacteremia.
Clinical uses of oxazolidinones
Reserved for management of serious or complicated infections caused by resistant organisms especially for infections where vancomycin or beta-lactams cannot be used. Treatment of VRE infections (bacteremia, UTI); nosocomial pneumonia due to MRSA.
Clinical uses of daptomycin
Reserved for treatment of serious/complicated infections caused by resistant gram-positive bacteria where vancomycin and/or linezolid cannot be used. Staphylococcus aureus bacteremia and endocarditis. Serious infections due to VRE. Should NOT be used for treatment of pneumonia since the compound is inactivated by pulmonary surfactant.
Clinical uses of lipoglycopeptides
Reserved for infections due to resistant gram-positive organisms where vancomycin, linezolid/tedizolid, and daptomycin cannot be used. Used in skin infections.
Major AEs of vancomycin
red man syndrome – related to the rate of vancomycin infusion (faster than 15 mg), to minimize vancomycin doses of 1 gram should be infused over at least one hour and larger doses should be infused over 90-120 minutes. Nephrotoxicity (reversible) and ototoxicity (irreversible). Dermatologic – hypersensitivity reactions. Hematologic – neutropenia, thrombocytopenia.
Major AEs of quinupristin-dalfopristin
phlebitis (venous irritation), GI, myalgias, arthralgias, rash.
Major AEs of oxazolidinones
GI, CNS, thrombocytopenia and anemia.
Major AEs of daptomycin
GI, HA, injection site reactions, rash, myopathy and CPK elevations, acute eosinophilic pneumonia.
Major AEs of lipoglycopeptides
: Infusion related reactions (red man syndrome - all); nephrotoxicity (telavancin)– higher in patients with comorbidities predisposing to renal dysfunction (renal disease, diabetes, CHF, HTN), receiving other nephrotoxins (NSAIDs, loop diuretics, ACE inhibitors), and patients > 65; QTc prolongation (telavancin); taste disturbances (telavancin, metallic/soapy).
1. Telavancin is pregnancy category C: black bow warning, pregnancy test needed before use in women of childbearing potential.
Major drug interactions associated with quinupristin-dalfopristin
Cytochrome P450 3A4 inhibitor – enhances serum concentrations of other drugs: lipid lowering agents (HMG-CoA reductase inhibitors), immunosuppressive agents (cyclosporine, tacrolimus), carbamazepine.
Major drug interactions associated with oxazolidinones
Weak inhibitors of monoamine oxidase potential for drug interactions increase pressor response, risk of serotonin syndrome in patients receiving concomitant serotonergic agents (SSRIs).
Major drug interactions associated with daptomycin
HMG-CoA reductase inhibitors (statins) – may lead to increased incidence of myopathy.
Major drug interactions associated with lipoglycopeptides
Telavancin and oritavancin interfere with results of coagulation tests – prothrombin time, INR, PTT, because they bind to and prevent the action of phospholipid reagents, which activate coagulation in many coagulation tests.
