Transcript Vancomycin monitoring : One or Two Serum level?

Vancomycin monitoring :
One or Two Serum levels?
Syamhanin Adnan
Pharmacy Dept,
Hospital Sungai Buloh
Introduction
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Vancomycin is a glycopeptide, first isolated from a strain of Streptomyces
(now Amycolatopsis) orientalis from a sample of dirt send to scientist at Eli
Lily ,found in a Borneo jungle in the mid-1950s
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Approved for use by FDA (USA) in 1958 for treating penicillin-resistant
Staphylococcus aureus infection.
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Initially isolated from soil in Borneo and India and was nicknamed “ Mississippi mud” due to
its color from impurities
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Methicillin, first semi-synthetic penicillin was also approved in 1958,
effective and less toxic option than vancomycin
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Vancomycin as an alternative therapy in patients allergic or intolerant to
other class of antibiotic
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Emergence of MRSA led to resurgence interest in vancomycin as the gold
standard of treatment
Mechanism of action
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Large molecule – complex glycopeptide with a molecular weight of
approximately 1,500
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Bactericidal – inhibit biosynthesis of bacterial cell wall, earlier crucial site
than penicillin; no cross resistance
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Active against most gram positive organism except enterococci (only
bacteriostatic)
Pharmacokinetic properties :
Key parameters
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Bioavailability
Volume of distribution
Clearance
Half-life
Therapeutic plasma concentration
Bioavailabiliy and Distribution
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Absorption
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Less than 5%, poorly absorbed from gastrointestinal tract
Presence of inflammatory bowel may increase absorption
Distribution
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Vd = 0.5 – 1.0 L/kg
30-55% protein bound
Diffuse well into pleural, pericardial, synovial and ascitic fluid
Penetration into CSF is not reliable or predictable, therapeutic concentrations may be
reached in patients with a acute meningitis
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Case report of intraventricular infusion of 10mg daily resulted in vancomycin level in CSF of 606mcg/ml following 9
days of treatment in 50 y/o male with infected intracerebral hematoma. It is suggested that lower dose may be
indicated and ventricular CSF levels to be determine with vancomycin intraventricular therapy.
Poor penetration into solid organ, 20-30% vancomycin serum concentration is
achieved in lung tissue
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A co-prescription of rifampicin as dual therapy has been suggested, but because it can cause
resistance, high dose vancomycin aiming for trough of more than 20mg/L has been advocated
(Jason A. Roberts; Jeffrey Lipman, Antibacterial Dosing in Intensive Care : Clinical Pharmacokinetics 2006: 45(8)
Clearance and Half-life
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Clearance
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Eliminated primarily by renal route (80-90% as unchanged)
CLvanco ~ CLcr
Some studies shown 17% of vancomycin is removed during
hemodialysis, in CAPD-small but continuous; drug loss is significant
Half-life
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5-10 hours
5 x half life to reach steady state ; 25 – 50 hours
ESRF : may approach 7 days
Normal renal function : interval of 8 – 12 hours
Therapeutic plasma
concentration :
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Therapeutic range of vancomycin was established in 1980s in
healthy subjects who received 500mg of vancomycin yielding peak
concentrations of 20 -40mg/L and trough concentratons of 5 –
10mg/L
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Even though limited data exist to demonstrate a correlation between
serum concentration and clinical success, routine drug monitoring
based on rational of targeting the MBC (4-5x MIC) while reducing
the potential renal adverse effects and ototoxicity
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Serum levels of antibiotics must be high enough to kill the infecting
organism and prevent further growth
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Inadequate dosing and failure to sustained serum concentration may
lead to increased resistance, progression of infection and higher
mortality.
Peak and trough levels :
FIGURE 1. Vancomycin elimination: portrayed is a
hypothetical concentration/time curve for a patient
receiving vancomycin. During the distribution phase,
serum concentration drops rapidly. This
characteristic makes peak concentration monitoring
at steady state extremely difficult. After distribution,
the drug is cleared in a linear fashion. Multiple
samples from this period may be helpful in predicting
individual dosage regimens. Trough levels, taken
immediately before a subsequent dose, assure that
the MIC is exceeded and are most predictive of
clinical efficacy.
From: Tam: J Intraven Nurs, Volume
22(6).November/December 1999.336
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Peak level obtain during distribution phase probably will be lower, small variation
in timing result large differences in measured peak level
Peak level must be obtained after the distribution phase is completed, allowing
single compartment pharmacokinetics
It is recommended to obtained 1- 2 hours after a one hour infusion
Peak level and concentrationdependent antibiotic:
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Levels obtained and pharmacokinetic calculations as an adjunctive
guide to the determination of dosing regimen, originally based on
models used for aminoglycosides (concentration-dependent
antibiotic), peaks to be therapeutically important for concentrationdependent antibiotic
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Some data suggest bactericidal activity of vancomycin is not
concentration-depedent Wilhelm, Mark P.M.D; Estes, Lynn Pharm. D; Mayo Clinic Proceedings : Vancomycin,
Volume 74(9) , September 1999, pp 928-935
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At concentration more than 5mg/ml (exceed minimal bactericidal concentration or 4-5 x MIC), further
increase do not increase killing rate, time during which concentration exceeds MIC is important
(T>MIC)
Studies suggest duration in vitro PAE is about 1.5-3 hours against S. aureus, may be longer in vivo
PAE allows longer interval for certain antibiotic (daily dosing aminoglycoside) but PAE for
vancomycin is rather short (1.5 to 3 hours)
Peak level is not useful for vancomycin since it is not
concentration-dependent?
One or Two Serum Levels ?
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Based on principles that vancomycin therapy requires sustained
therapeutic concentration while avoiding high peaks, it is
recommended that optimal vancomycin levels could be ensured by
measuring trough levels alone (Saunders NJ. Why monitoring peak vancomycin concentrations? Lancet
1994;344:1748-50)
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“Traditional" trough concentrations of 5 to 10 mcg/mL are being
reconsidered, evidence of increasing minimum inhibitory
concentrations (MICs) of staphylococci to vancomycin
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A prospective cohort study done by Hidayat et al (2006) of adult patients infected with MRSA at Huntington
Hospital (from August 2004 through June 2005) was performed to determine the distribution of vancomycin
MIC. Of 95 patients, 54% (n=51) were infected with high MIC strains (MIC of >=2mcg/ml) and 77% of this
group of patients had pneumonia and/or bacteremia.
Higher trough concentrations (15 to 20 mcg/mL) are recommended
in settings such as nosocomial and ventilator-associated pneumonia
and in deep-seated staphylococcal infections (eg, endocarditis,
prosthetic joint infections, CNS infections).
American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired,
ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388.
Monitoring trough levels : Does it prevent
drug toxicity and/or ensures therapeutic
dosing of the drug ?
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Vancomycin is now considered a relatively safe and tolerable drug.
The original vancomycin preparation (‘Mississipi mud’) contained
impurities that was associated with local and systemic reactions.
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including venous irritation, chills, rash which were primarily infusion-related or attributed to
contaminants in the manufacturing process
Improved purification procedures seem to have diminished the local toxicity associated with
vancomycin
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Two systemic adverse events continuted to complicate the use of
vancomycin: nephrotoxicity and ototoxicity, monitoring it’s level
(trough) has been a common practice
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A recent large retrospective review of patients with MRSA health
care – associated pneumonia suggested that aggressive dosing
strategies to achieve trough level of more than 15mcg/ml may not
offer any advantage over traditional dose target (5 to 15mcg/ml)
(Jeffres et al, Predictors of mortality for MRSA health-care associated pneumonia : specific evaluation of vancomycin pharmacokinetic indices. Chest
2006 Oct ;130(4):947-55)
Serum levels :
Correlation with efficacy and toxicity
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Iwamoto et al (2003) conducted a retrospective study from 184
patients with MRSA infection receiving IV vancomycin,
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Significant decrease in creatinine clearance in patients (n=111) did not receive TDM when
compared with patients (n=73)received TDM during vancomycin therapy (p<0.05)
No significant difference in cumulative dose and duration of therapy in subgroup analysis in
patients with MRSA bacteremia or pneumonia between those who received TDM (n=46) and
not monitored (n=53)
Karam et al (1999) conducted a study comparing restrospective
patients monitored with dosing adjustment (n=120) with a group of
prospective patients (n=120) dosed using nomogram.
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No statistical difference in both group with respect to organism eradication, cure,
improvement, failure or toxicity
Patient population was young and nomogram was reliable for patients with creatinine
clearance above 60ml/min
Serum levels :
Correlation with efficacy and toxicity
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In-vitro vancomycin susceptibility study by Sakoulas et al. (2004)
examines 30 different MRSA isolates from 30 patients with known
clinical outcome in phase II and phase IV RCT to determine
relationship between bactericidal activity and outcome
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Authors speculate that wide varying vancomycin levels (without regards to peak
or trough) required to successfully destroy the isolates during laboratory
testing~might explain mixed therapeutic effectiveness results observed in clinical
outcome of vancomycin
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Whether MIC should be measured and reported after initiation of vancomycin
therapy ?
Peak level :
To be obtained or predicted ?
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Based on principles that optimal vancomycin level could be ensured
by measuring trough levels alone, a study was conducted by AndrAs
et al (1997) to assess the performance of one-compartment
Bayesian forecasting method to estimate vancomycin peak level on
the basis of a single trough sample
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Involves 79 adult patients with two measured vancomycin concentrations (C2h
and Cmin). C2h were compare with prediction value using Bayesian forecasting
method
The predicted peak level (C2h) were not significantly different from the observed
and could be used to estimate vancomycin concentrations at 2 hours after dosing
using only trough sample
However, all predictions were from normal renal function in steady state
conditions
AndrAs et al, Therapeutic Drug Monitoring : Vancomycin Monitoring : One or Two Serum Levels ?, Volume 19(6)
Decemeber 1997, pp 614-619
Peak level :
To be obtained or predicted ?
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In another study conducted by Fofah et al (1999), involves 100 paired
vancomycin concentrations in 87 infants to compare peak and trough values
to yield a formula ( to predict vancomycin from trough) and later part was to
evaluate the prediction formula
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The peak vancomycin concentrations were weakly correlated with the values
calculated using the prediction formula obtained
Authors conclude that peak vancomycin concentrations cannot reliably predicted
from trough in neonatal clinical practice
Fofah et al, The Pediatric Infectious Disease : Failure of Prediction of Peak Serum Vancomycin Concentrations
from Trough Values in Neonates, Volume 18(3), March 1999, pp 299-301
Nomogram vs
pharmacokinetic calculation
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Various nomogram are available for empiric dosing based on
population pharmacokinetics, useful before patient-specific
pharmacokinetic parameters become available
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May not work well in anuric patients or patients with rapidly
changing renal function, in which serum drug level is used to
adjust doses in these patients
Fig. 1 Moellering vancomycin nomogram for patients with reduced
renal function. Reprinted with permission from Ann Intern Med.9
From: Levine: South Med J, Volume 101(3).March 2008.284-291
Table 4.-Mayo Medical Center Vancomycin Dosing Nomogram
From: Wilhelm: Mayo Clin Proc, Volume 74(9).September
1999.928-935
Peak level
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Lack of evidence that toxicity associated with peak levels
Difficulty in interpreting peak level because of non-compartmental
model
If trough levels are in therapeutic range, it is unlikely peak levels
would be above 40mcg/ml
It may be reasonable to perform intensive monitoring in high-risk
patient and patients who have a poor therapeutic response
Peak level should be consider if therapy is prolonged and to confirm
adequate serum concentrations into infection sites with limited
vancomycin penetration
Richard H Drew, PharmD, MS, BCPS
Trough level
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Adequate trough levels may be associated with efficacy whereas
high trough may increase the risk of nephrotoxicity
Which trough level to be targeted ?
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Higher trough concentrations (15 to 20 microgram/mL) are recommended in
settings such as nosocomial and ventilator-associated pneumonia and in deepseated staphylococcal infections (eg, endocarditis, prosthetic joint infections, CNS
infections)
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Prevalence of MRSA strain of elevated MIC probably requires aggressive
vancomycin dosing to achieve a trough greater than 15mcg/ml
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Data on MIC of our MRSA strain ? If our MRSA strain is reported as strain of
elevated MIC, probably it would warranted higher trough target
Vancomycin dosing and serum
concentration monitoring in adults – update
Richard H Drew, PharmD, MS, BCPS
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Monitoring not required
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Trough level
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IV treatment less than 4 days
IV treatment >4 days
End-stage renal disease and are likely to receive more than one dose
Receiving other nephrotoxic drugs (eg, cyclosporine A, amphotericin B,
aminoglycosides)
Morbid obesity
Rapidly changing or unpredictable renal function
Peak and trough level
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IV treatment >4 days
Selected infections (eg, endocarditis, osteomyelitis, CNS infections), which
require confirmation of serum concentrations of vancomycin within the upper
therapeutic range
Dosing strategies to sustain
T>MIC
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Sustained therapeutic concentration (T>MIC) may be achieve with
continuous infusion/more frequent dosing
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A study done by M.D Kitzis and F.W.Goldstein (2006) comparing
continuous infusion of vancomycin (loading dose of 1g and total of
2-6g daily) with conventional dosing (2x1g or 4 x 500mg) in 1737
patients, trough serum were determined after 36-48h
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For fully susceptible MRSA infection (MIC less than 4mg/L), 19% of conventional
dosing and 7.9% of continuous infusion failed to receive adequate dose (trough
level below 15mg/L).
Therapeutic failure increase in GISA (glycopeptide-intermediate S. aureus).
87.8% and 79.1% in conventional dosing and continuous infusion respectively.
M.D Kitzis and F.W.Goldstein, European Society of Clinical Microbiology and Infectious Disease : Monitoring of vancomycin
serum levels for the treatment of staphylococcal infections, volume 12 Number 1, January 2006, pp 81-95
Risk factor associate with
treatment failure
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A retrospective case-control study was performed at Fletcher Allen
Health Care (FAHC) in Burlington, Vt, to examine factors associated
with persistent MRSA bacteremia, all episodes of MRSA bacteremia
from 1998 to 2004 were reviewed.
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Cases of persistent MRSA bacteremia were defined as having an initial positive
MRSA blood culture and at least 1 positive MRSA blood culture drawn 5 or more
days after beginning treatment with intravenous vancomycin
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A control was defined as a patient who had an initial positive MRSA blood culture,
no further positive MRSA blood cultures 48 hours or more after beginning
treatment with intravenous vancomycin, and at least 1 follow-up negative blood
culture.
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Of 251 MRSA bloodstream infections, 20 patients met the case definition and
were compared with 40 patients who met definitions as controls were randomly
selected
Bessette, Erika L. PharmD*; Ahern, John W. PharmD, BCPS*†; Alston, W. Kemper MD, MPHâ€, Infectious Disease in Clinical Practice :Risk
Factors for Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia Despite Treatment With Vancomycin Volume 15(3), May 2007, pp
174-177
Risk factor associate with
treatment failure
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The median number of foreign devices, an intravascular device or
septic phlebitis as a site of infection, and a maximum vancomycin
minimum inhibitory concentration of 2 µg/mL were significantly
associated with persistent bacteremia.
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Authors conclude that the relationship between the vancomycin MIC
and treatment outcome and the changes in the MIC during therapy
warrant further investigation.
Bessette, Erika L. PharmD*; Ahern, John W. PharmD, BCPS*†; Alston, W. Kemper MD, MPHâ€, Infectious Disease in Clinical
Practice :Risk Factors for Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia Despite Treatment With
Vancomycin Volume 15(3), May 2007, pp 174-177
Pharmacokinetic calculation in
HSB
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Manual process in HSB, both peak and trough level is needed in
the manual pharmacokinetic calculation to recommend a dosing
adjustment
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Patient most likely to require vancomycin plasma concentration
monitoring are those at highest risk of therapeutic failure or
potential drug toxicity
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If trough level is inadequate/patient response suggest treatment
failure and a dosing adjustment is highly recommended, both
peak and trough level is probably necessary
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Otherwise, monitoring only trough level is sufficient
Conclusion
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Trough level closely related to MIC, 4-5 times above MIC, current
practice do not measure MIC and is not reported after initiation of
vancomycin therapy
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Existing evidence does not seem to support routine serum
therapeutic monitoring (peak level) for vancomycin dosing to
improve clinical outcome
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However, regular monitoring to allow dose adjustment in patients
with renal dysfunction and those receiving nephrotoxic agents or at
risk of treatment failure is still recommended
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This topic clearly the focus of debate and merits regular surveillance
to gauge on how the literature on this issue develops over time