IID 07: Therapeutic Drug Monitoring of Vancomycin Flashcards
What type of molecule is vancomycin?
glycopeptide
What is the mechanism of action of vancomycin?
- binds to peptidoglycan precursor – D-alanyl-D-alanine terminating pentapeptide
- inhibits monomers into peptidoglycan chain – disrupts cell wall synthesis
What are the clinical indications for vancomycin?
- endocarditis, osteomyelitis, pneumonia, soft-tissue, severe/life-threatening infections
- CNS, febrile neutropenia, line infections, prosthetic joint infection, surgical prophylaxis
- C. difficile infection
How are the terms bactericidal and bacteriostatic determined?
in vitro activity based on:
- minimal inhibitory concentration (MIC)
- minimal bactericidal concentration (MBC)
bactericidal: MIC and MBC are close together
bacteriostatic: MIC and MBC are far apart
Is vancomycin bactericidal or bacteriostatic?
bactericidal
Why do clinicians feel that vancomycin is bacteriostatic?
- works slowly – big molecule
- see other factors
What factors affect vancomycin activity?
- bactericidal (MIC/MBC) – 4-5x MIC of pathogen for activity to be optimized
- time-dependent kill
- bacterial burden – size, growth phase (stationary, exponential)
- clinical activity
- penetration into tissues – inflammation
LO: What is vancomycin?
- effective for treatment of infections caused by Gram-positive organisms (including S. aureus, Strep, and Enterococcus)
- bactericidal drug
- numerous factors affect its activity
- concentrations < 4-5x MIC are considered bacteriostatic
What are the pharmacokinetic properties of vancomycin?
- multi-compartmental (2-3 compartments) – but assume 1-compartment model
- protein binding ~50%
- volume of distribution ~0.6 L/kg (0.5-0.9 L/kg)
- ~90% renally eliminated unchanged via glomerular filtration
- t1/2 ~6 h (normal renal function)
- first-order kinetics
Why is vancomycin assumed to be a 1-compartment model?
- multi-compartment distribution occurs only in < 10% of overall AUC
What is time-dependent (concentration-independent) kill?
- if vancomycin is not given, bacteria continues to grow
- if vancomycin concentration is increased above MIC of organism, pathogen starts to grow more slowly and peaks at around 4-5x above MIC
What is AUC/MIC?
best predictor of activity – in pharmacokinetic/pharmacodynamic model, AUC/MIC ratios of > 400-600 enhance efficacy
- difficult to calculate AUC/MIC clinically – trough used as surrogate marker, BC guidelines recommend troughs of 10-15 mg/L, IDSA guidelines recommend 15-20 mg/L for severe infections, maintain concentrations 4-5 times MIC (lower MICs resistance)
- higher concentrations required for sequestered infections – CNS infection and pneumonia
LO: What are the pharmacokinetic/pharmacodynamic properties of vancomycin?
- first-order kinetics
- Vd ~0.6 L/kg (0.7 L/kg)
- t1/2 ~6h
- AUC/MIC 400-600 is the best pharmacokinetic-pharmacodynamic predictor of activity
- target trough is 10-15 mg/L (BC Guidelines)
- time-dependent kill (concentration-independent kill) antibiotic
- activity peaks at 4-5 times MIC
What are the ASHP/IDSA/SIDP guidelines for dosing adult patients?
- weight-based: 15-20 mg/kg/dose every 8-12 hours (usual dose is 15) – less frequent dosing if there are renal complications
- serious/complicated infections: loading dose of 20-35 mg/kg actual body weight (usually 25 mg/kg) – load gives higher concentration at start of treatment, and arrives at therapeutic levels quicker
What are serious MRSA infections?
- bacteremia
- sepsis
- infective endocarditis
- pneumonia
- osteomyelitis
- meningitis
What are the ASHP/IDSA/PIDS/SIDP dosing guidelines for serious MRSA infections?
AUC/MIC target of 400-600 (assuming vancomycin MIC of 1 mg/L) for clinical efficacy and patient safety
LO: How do we dose vancomycin?
numerous methods to dose vancomycin
conventional dosing regimen for adult patients:
- weight-based: 15 mg/kg/dose every 8 to 12 hours
- for more severe infections: 20 mg/kg/dose
- dose every 8 hours for younger patients
- use longer dosing intervals for older patients
conventional dosing regimen for complicated infections:
- loading dose of 20-35 mg/kg (usually 25 mg/kg)
(actual body weight)
conventional dosing regimen:
- trough: 10-15 mg/L (BC guidelines)
- peak: 20-40 mg/L
- serious MRSA infections: AUC/MIC of 400-600
What contributed to adverse reactions of vancomycin?
- impurities contributed to adverse reactions
- purity increased from 1960-1980s – and adverse events decreases
What are the adverse effects of vancomycin?
- fever, chills, phlebitis
- vancomycin flushing syndrome or vancomycin infusion reaction (formerly red man syndrome) –histamine release reaction (not allergy)
- neutropenia
- ototoxicity
- nephrotoxicity
What is neutropenia?
absolute neutrophil count > 1000 cells/mm3
- 2-8% incidence
What is the proposed mechanism of neutropenia?
- immune destruction of neutrophils – suppression of bone marrow
- not completely related to daily dosages, total cumulative dosage, or supratherapeutic vancomycin levels
- likely associated with therapy > 10 days (> 20 days)
What are the recommendations for vancomycin and neutropenia?
- monitor WBC count with differential (including absolute neutrophil count) once weekly if > 7 days
- discontinue vancomycin and initiate alternative agent
What is ototoxicity?
damage to cochlea or auditory nerve
- 1-9% incidence
- true risk low without ototoxic agents
What is the proposed mechanism of ototoxicity?
- damages high frequency sensory hairs in cochlea, then middle and low frequency hairs – high-tone deafness occurs before low-tone deafness, permanent hearing loss
- associated with higher dose and increasing age
What is nephrotoxicity?
> 0.3 mg/dL (26.5 μmol/L) over 48 hours, OR SCr 1.5-1.9x baseline, OR GFR decreases by > 50% from baseline
- usually 4-7 days
- 0-17% vancomycin monotherapy incidence – uncommon with typical regimens, > 4g/day increases risk (?)
- 7-43% with concomitant aminoglycoside – 3-4x increase
What is the proposed mechanism for nephrotoxicity?
stimulates oxygen consumption and ATP in proximal tubule
- oxidative stress damages glomeruli and proximal tubules
- this is corrected once you stop taking the drug
LO: What are the toxicities of vancomycin?
- impurities contributed to initial adverse reactions
- toxicities unrelated to serum concentrations: fever/chills/phlebitis, vancomycin flushing syndrome or vancomycin infusion reaction, neutropenia
- toxicities associated with serum concentrations (low incidence with monotherapy): ototoxicity, nephrotoxicity
What was the ototoxicity evidence for vancomycin levels?
- serum vancomycin concentration 80-100 μg/mL
- associated with concentrations above 40 μg/mL
What was the nephrotoxicity evidence for vancomycin levels?
- associated with troughs > 10 μg/mL
What was the efficacy evidence for vancomycin levels?
- levels that can be achieved in normal patients
LO: What was the evidence for vancomycin levels?
- evidence for TDM was controversial with most of the literature published before the concepts of “EBM” and optimal dosing based on AUC/MIC
- initial toxicities prompted “TDM for all”
- dosage of 1 g q12h was considered “effective” (and the concentrations achieved in healthy adults were regarded as “therapeutic”)
How should we dose vancomycin now?
Loading Dose
- LDs may more rapidly attain of vancomycin troughs of 15-20 mg/L in adults, but information in pediatrics, obesity, and renal impairment limited
- vancomycin LDs of 25-30 mg/kg may be considered in adults with serious infections
How should we dose vancomycin now?
Continuous Infusion
- unlikely to improve outcome
- based on limited data, new guidelines suggest continuous infusion if AUC targets are not achievable
LO: How should we dose vancomycin now?
- AUC/MIC is best PK/PD parameter – AUC/MIC 400-600 (trough of 10-15 mg/L)
- MIC of 2 μg/mL is more difficult to treat
- paradigm shift – dosing and monitoring for efficacy rather than toxicity
LO: What are the doses for vancomycin now?
- new target trough of 10-15 mg/L (BC guidelines) – note: previous target dose was 10-15 mg/L for mild infections and 15-20 mg/L for severe infections)
- loading dose of 20-35 mg/kg may be considered in seriously ill (usually 25 mg/kg)
- for MIC >2 mg/L: AUC/MIC > 400 is not achievable with conventional dosing methods if renal function is normal – consider alternate agents (daptomycin, linezolid, ceftaroline, ceftobiprole, tigecycline)
LO: When should we do no vancomycin levels (no risk factors)?
- adults < 60y, CrCl > 40 mL/min, < 7 days
LO: When should we do trough vancomycin levels (with risk factors)?
- 7 days; or > 72 hours if aggressive dosing, unstable renal function, dialysis, risk of toxicity (concurrent nephrotoxins/ototoxins), frail elderly, hypermetabolic, low body weight, obesity, septic shock, unresponsive to treatment
LO: When should we do peak and trough vancomycin levels?
- severe infections, concomitant nephrotoxic and/or ototoxic agents, unstable renal function, obesity, pregnancy, and pediatrics
- may consider drawing peaks to calculate pharmacokinetic parameters to optimize dosages, rather than for targeting a specific peak
LO: When trough levels should we target?
10-15 mg/L in both uncomplicated and severe infections (new BC guidelines)
- note: trough levels are taken within 30 minutes prior to the next dose
- [peak 20-40 μg/mL (at 1 hour after end of 1-1.5 hour infusion)] – note: some institutions use a 3 hour peak level after 1-1.5 hour infusion
LO: What should be done prior to doing vancomycin levels?
- identify early on, if dose requires escalation
- prevent perpetuation of dosing error
- initial calculation of pharmacokinetic parameters to avoid further chasing of levels
- estimate renal function (ie. pediatrics)
LO: When should we do vancomycin levels?
Controversies with IDSA Guidelines
- recommend higher troughs (15-20 mg/L)
- BC guidelines target lower troughs of (10-15 mg/L)
LO: What are the optimal dosing and monitoring strategies for vancomycin?
– see notes
KEY NOTES (next cards)
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