14 Vancomycin, Telavancin, Aminoglycosides, Polymyxins Minejima Flashcards Preview

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Flashcards in 14 Vancomycin, Telavancin, Aminoglycosides, Polymyxins Minejima Deck (65):
0

What is Vancomycin?

A large complex, tricyclic antibiotic with a molecular mass of 1,500 Da. Contains a glycosylated hexapeptide chain rich in unusual amino acids (Glycopeptide)

2

What is Vancomycins MOA?

Inhibits peptidoglycan synthesis and assembly. Acts as a specific peptide receptor by binding with high affinity for the D-alanyl-D-alanine terminus of cell wall precursor units --> inhibits peptidoglycan synthesis --> bactericidal. Rate of inhibition is much slower than with B-lactam agents

3

What is Vancomycins spectrum of activity?

Narrow-spectrum: Gram (+) bacteria: S. aureus, S. epidermidis, Streptococci, Enterococci, Corynebacterium, Clostridium difficile. NO Gram (-) activity

4

What are the clinical use indications for Vancomycin?

Infections d/t MRSA, S. epidermidis (prosthetic device infections). Penicillin-resistant Streptococci, Enterococci. C. difficile colitis (PO) failing metronidazole or life-threatening. Patients infected with Gram (+) bacteria with allergy to PCNs and CEPHs. Prophylaxis for surgical procedures involving prosthetic device or endocarditis per AHA

5

What is Vancomycin NOT recommended for?

Routine surgical prophylaxis. Empiric therapy for febrile neutropenia, unless patient has initial evidence of an infection caused by Gram (+) AND the prevalence of MRSA is high. Treatment of a single blood culture positive for coagulase-negative staphylococci, if other blood cultures taken during the same time frame are negative. Continued empiric use for presumed infections in patients whose CXs are negative for B-lactam resistant Gram (+) organisms. Systemic or local prophylaxis for infection/colonized of indwelling central or peripheral intravascular catheters. Eradication of MRSA colonization. Routine prophylaxis for patients on hemodialysis or ambulatory peritoneal dialysis. Use of vanco solution for topical application or irrigation. Treatment of infections caused by B-lactam sensitive Gram (+) organisms in patients who have renal failure

6

What is the resistance mechanism of vancomycin-resistant Enterococci and VRSA?

Vancomycin-resistant enterococci in the presence of vancomycin make cell-wall precursors that have low affinity for vancomycin (alter the "lock and key")

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What is Vanco-Resistant S. Aureus (VRSA)?

First clinical case demonstrating transfer of VRE resistance (vanA gene) to S. aureus through exchange of genetic material

8

What is Vanco-Intermediate S. Aureus (VISA)?

All developed from pre-existing MRSA strains. All had prolonged vanco therapy. Thickened cell wall, vanco unable to cross

9

What is the role of vancomycin vs. MRSA?

Increasing reports of treatment failure despite attaining therapeutic throughs. Emergence of clinical strains with reduced susceptibility (hVISA, VISA, VRSA)

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What are the characteristics of VRSA?

Rare; MIC 32-1028 mcg/ml. Fully resistant likely; vanA operon acquired from VRE. Patients infected with both MRSA and VRE

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What are the characteristics of VISA?

MIC 4-16 mcg/ml, "intermediate" R. Overproduce a matrix that captures vanco and keeps it from entering the cell; "thickened" cell wall on electron microscopy. Patients have had long term vancomycin therapy

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What are the characteristics of Vanco tolerance?

MBC:MIC > 32; "stunted" not killed

13

What are the characteristics of hVISA?

MIC in "S" range: 0.5-8 mcg/ml. Prevalence 2-76%; not detected by routine tests. Accounts for treatment failure to vanco vs. "S" strains

14

What is the lab detection problem with hVISA?

Available tests do not reliably detect resistance. The MIC will show on an E-test, but there will still be some small random colonies in the zone of inhibition

15

What are the MIC breakpoints for S. aureus?

S: < 2, I: 4-8, R: > 16

16

What is the IV dosage like for Vancomycin?

"Usual" daily dosage, need to calculate based on renal function to achieve "target" levels. Adults: 20-30 mg/kg/d (10-15mg/kg Q6h to Q12h). Children: 40 mg/kg/d (10mg/kg Q6h or 15mg/kg Q8h)

17

What is the PO dosage like for Vancomycin?

125-500mg Q6h (for C. difficile colitis ONLY!)

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What can happen with rapid IV infusion of Vancomycin?

Red-man syndrome. Dilute to 100-250 mL; doses 0.5-1g infuse over 60 min at least. Relates to histamine release

19

What is the PK of vancomycin like?

F < 5%; may reach therapeutic serum concentration in presence of inflammatory bowel disease and renal failure. CSF penetration variable, meningitis requires intrathecal administration (5mg). Elimination by GF almost exclusively (dose adjustment needed). T1/2 normal: 6-8 hrs; anuric ~7.5 days

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What is the PD of vancomycin like?

Time-dependent killing, moderate persistent effects. Maximal bactericidal activity at 4-5x MIC or AUC/MIC 400. Target trough levels based on sensitivity of organism and severity of infections

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What is the goal PD of vancomycin?

Maintain unbound levels 4-5x above MIC throughout dosing interval or AUC/MIC 400

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What is the trough target for vanco at MIC 1?

Trough target 10 mg/L accounting for 50% ppb

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What is the trough target for vanco at MIC 2?

Trough target 15-20 mg/L. Higher concentrations for deep tissue infections, endocarditis, meningitis, osteomyelitis

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What are the ADRs of Vancomycin?

Red-man syndrome. Ototoxicity. Nephrotoxicity. Hypersensitivity reactions: rash, anaphylaxis

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What is Red-Man Syndrome?

Flushing of the face, neck and thorax, increased HR, decreased BP. Caused by rapid infusion rate, large dosage. Histamine-release (NOT allergic hypersensitivity)

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How do you manage Red-Man Syndrome?

Prolong infusion time, dilute concentration, premedicate with diphenhydramine

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What is Nephrotoxicity like with Vancomycin?

Gradual onset, reversible. Increased risk with concurrent nephrotoxins or vasopressors. Increased risk with treatment duration

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What is Telavancin?

Lipoglycopeptide. Used for treatment of adults with complicated skin and skin structure infections caused by Gram (+) bacteria

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How is the structure of Telavancin vs. Vancomycin?

Telavancin has a hydrophilic side chain that helps bind to D-ala-D-ala as well as a hydrophilic addition to increase kidney excretion

30

What is the MOA of Telavancin?

Concentration-dependent, rapidly bactericidal. "Dual Action". 1) Inhibits late-stage bacterial cell wall synthesis thru tight binding to D-ala-D-ala containing peptidoglycan precursor (10-fold more potent than vanco in peptidoglycan synthesis inhibition). 2) Changes bacterial cell membrane potential and permeability

31

What is Telavancin's spectrum of activity?

S. aureus (including MRSA, hVISA, VISA), S. epidermidis, Streptococci (PCN-R Strep pneumoniae, S. pyogenes, S. agalactiae). Enterococci (vanco-susceptible). Gram (+) anaerobes: C. perfringens, C. difficile, Peptostreptococcus). NO activity against Gram (-) pathogens

32

What is the PK/PD like for Telavancin?

Cmax: 108 +/- 26 mcg/ml. T1/2 = 7-9 hr --> QD dosing. Eliminated by kidneys primarily (80%). NOT metabolized; no effect on CYP450 isoenzymes

33

What is dosing like for Telavancin?

10mg/kg over 60 mins Q24h. Lower efficacy in patients with CrCl < 50. Formulated in hydroxypropylcyclodextrin - can accumulate in renal failure - renal toxicity. Single dose vials: 250mg, 750mg

34

How is Telavancin dosed for renal dysfunction?

CrCl 30-50: 7.5mg/kg Q24h. CrCl 10-30: 10mg/kg Q48h. HD or ESRD: not recommended

35

What is the BBW associated with Telavancin?

Contraindicated in pregnancy. Digit and limb malformations, reduced fetal weights. Serum pregnancy test in women of childbearing age prior to use

36

What are the ADRs associated with Telavancin?

Nephrotoxicity. QTc prolongation (avoid in uncompensated HF or severe left ventricular hypertrophy). Infusion-related "red-man" syndrome. Coagulation test interference (obtain PT, INR, aPTT, clotting time, Factor Xa test close to trough/next dose), does not interfere with coagulation

37

What are the aminoglycosides used?

Streptomycin, Gentamicin, Tobramycin, Amikacin, Netilmicin

38

What are the general characteristics of Aminoglycosides?

All contain two or more amino-sugar residues linked to a central, six-membered, aminocyclitol ring by glycosidic bonds polycations - polarity --> poor oral absorption, poor CSF penetration, rapid excretion by the kidneys

39

What is the MOA of Aminoglycosides?

Multifactorial process: Initial ionic interaction with external surface of the cell. Entry into cells. Binding to ribosomes

40

What happens with Aminoglycosides during the initial ionic interaction with external surface of the cell?

Disruption of biofilm by displacing Ca and Mg --> holes in the cell wall with disruption of the normal permeability of the cell wall

41

What happens with Aminoglycosides during entry into cells?

Diffuse through porin proteins. Energy dependent transport across the inner membrane requires a membrane potential (energy-dependent & oxygen-dependent) which can be blocked or inhibited by divalent cations (Ca and Mg), hyperosmolarity, a reduction in pH, and anaerobiasis

42

What happens when Aminoglycosides bind to ribosomes?

Binds to 30S ribosome and inhibit protein synthesis --> misreading and premature termination of translation of mRNA

43

What is the mechanism of resistance to Aminoglycosides?

Inactivation of the drug by microbial enzymes. Plasmid-mediated resistance. Enzymes phosphorylate, adenylate, or acetylate specific hydroxyl or amino groups of the AGs once they reach the periplasmic space. Impaired transport of drug into the cell (anaerobes are resistant due to a lack of the necessary transport system. Stenotrophomonas maltophilia, some Gram (+) cocci). Mutations affecting proteins in the bacterial ribosomes (specific for streptomycin (P. aeruginosa, enterococci))

44

Which Aminoglycosides is least vulnerable to resistance?

Amikacin, due to protective side chains

45

What are Aminoglycosides spectrum of activity?

Aerobic Gram (-) bacilli - Haemophilus sp, Enterobacteriacea, Pseudomonas aeruginosa. LIMITED Gram (+) cocci activity (not active when used alone, Gent > Tobra ~ Amikacin). Mycobacteria

46

What are the indications for Aminoglycosides use?

AG in combination with B-lactam agent = synergistic killing. Gram (-) bacteria: UTIs, pneumonia, peritonitis, endocarditis, sepsis. Gram (+) bacteria: bacteremia, endocarditis, meningitis due to enterococci, staphylococci, streptococci. Usually used in combo for Gram (+)

47

What is the PK of Aminoglycosides?

F < 5% (NOT given orally). Distributes freely in the vascular space and interstitial spaces of most tissues. Urine concentration exceed peak plasma levels 25-100x w/in 1 hr of drug administration, remain above therapeutic levels for days after multiple-dose regimen, with a terminal T1/2 of 48-200 hrs. Renal clearance ~ CrCl (GFR). T1/2 (beta) = 2 hrs. Significant Post Antibiotic Effect (PAE) ~ 2 hrs for GNRs

48

What is Extended-Interval Aminoglycoside Dosing?

PK + PD --> single larger doses at longer intervals to achieve greater efficacy and reduced toxicity. 1) Maximize early concentration that would achieve greater killing activity (peak to MIC ratio) without concern for subsequent period of sub-MIC levels. 2) Decrease renal cortical and inner ear tissue uptake of AG since the process is saturable, thereby reducing nephrotoxicity and ototoxicity

49

For Aminoglycosides tissue/fluid penetration, where are high concentrations found?

Renal cortex. Inner ear (lymph)

50

For Aminoglycosides tissue/fluid penetration, where are equal concentrations found?

Pleural. Synovial. Peritonea (70%)

51

For Aminoglycosides tissue/fluid penetration, where are low concentrations found?

Bile. Respiratory secretions. CSF. Ocular fluids

52

What are the ADRs associated with Aminoglycosides?

Ototoxicity (auditory, vestibular dysfunction). Nephrotoxicity. Neuromuscular blockade

53

What are the characteristics of Ototoxicity caused by Aminoglycosides?

Incidence ~25%; irreversible. From cumulative exposure. Auditory: high-frequency hearing loss - audiometry. Vestibular: N/V and difficulty with equilibrium, vertigo

54

What is Ototoxicity like for the different Aminoglycoside agents?

Preferential toxicity with specific agents. Streptomycin and Gentamicin - vestibular. Amikacin - auditory. Tobramycin - both equally

55

What are the characteristics of Nephrotoxicity caused by Aminoglycosides?

Onset ~day 5 of therapy. Caused by elevated trough, cumulative exposure (duration of therapy). Variable nephrotoxic potential for individual agents (neomycin > gentamicin ~ tobramycin > streptomycin). Higher risk w/ concomitant nephrotoxin (vancomycin, amphotericin, foscarnet, radiocontrast). Reversible. Extended-interval dosing delays onset

56

What are the characteristics of Neuromuscular Blockade caused by Aminoglycosides?

Rare; prolonged muscular paralysis and apnea. Disease state and/or a concomitant drug interferes with neuromuscular transmission. Inhibit presynaptic release of ACh and blockage of postsynaptic receptor sites of ACh. Reversed rapidly by IV Calcium Gluconate. AGs contraindicated in patients with myasthenia gravis

57

How can Neuromuscular Blockade from Aminoglycosides be rapidly reversed?

IV Calcium Gluconate

58

What are Polymixins/Colistin?

Polymyxin B, Polymyxin E (Colistin). Use as topical unit recently due to emergence of multidrug-resistant organisms. Abandoned for systemic use due to nephrotoxicity, neurotoxicity

59

What is the MOA of Polymixins/Colistin?

Cationic "positively charged" antibiotic binds to lipopolysaccharide of the bacterial membrane of Gram (-) bacteria (negatively charged) --> disruption of the bacterial cell membrane, leakage of cell membrane and cell death

60

How can Intrinsic Resistance of Polymixins/Colistin happen?

Alterations in Lipid A --> reduced binding (example: Proteus mirabilis)

61

How can Acquired Resistance of Polymixins/Colistin happen?

Substitution of phosphate groups in lipopolysaccharide --> reduced anionic surface charges --> reduced binding

62

What is the spectrum of activity of Polymixins/Colistin?

Gram (-) bacilli (aerobes): Pseudomonas aeruginosa, Acinetobacter spp, Klebsiella spp, Enterobacter, E. coli, Citrobacter, Stenotrophomonas, Hemophilus, Salmonella/Shigella. NOT active against Gram (-) and Gram (+) cocci, GPR, all anaerobes. Intrinsic R: Proteus, Providencia, Serratia

63

What is the PK/PD of Colistin?

Bactericidal activity: AUC/MIC with modest PAE. T1/2 = 6h (48h anuric), poorly dialyzable. Concentrates in tissues but does not penetrate BBB in non-inflamed meninges

64

What are the different dosage forms of Polymixins/Colistin?

Topical. Irrigation solution. Intrathecal. Inhalation (cystic fibrosis). IV

65

What are the ADRs associated with Polymixins/Colistin?

Neurotoxicity (AVOID in patients w/ myasthenia gravis). Nephrotoxicity (onset within 1st 4 days). Inhalation (bronchospasm can last for 1/2h)