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Journal of Drug Design and Research

Cite this article: La MK, Ong A, Morbitzer K, Jordan DJ, Rhoney DH (2017) Vancomycin Pharmacokinetics in Neurocritically Ill Patients with Central Nervous System Infection. J Drug Des Res 4(7): 1061.

*Corresponding authorDenise H. Rhoney, Division of Practice Advancement and Clinical Education, University of North Carolina Eshelman School of Pharmacy, 115 Beard Hall, Campus Box 7574, Chapel Hill, NC 27599-7574, USA, Tel: 919-966-7318; Fax: 919-843-3861; Email: drhoney@unc.edu

Submitted: 15 November 2017

Accepted: 08 December 2017

Published: 09 December 2017

ISSN: 2379-089X

Copyright© 2017 Rhoney et al.

OPEN ACCESS

Keywords•Vancomycin•Central nervous system infection•Pharmacokinetics•Therapeutic drug monitoring

Short Communication

Vancomycin Pharmacokinetics in Neurocritically Ill Patients with Central Nervous System InfectionMary K. La1, Alvin Ong2, Kathryn Morbitzer3, J. Dedrick Jordan4, Denise H. Rhoney1*1Division of Practice Advancement and Clinical Education, University of North Carolina Eshelman School of Pharmacy, USA2US Medical Managed Care, Sanofi Genzyme, Cambridge, USA 3Department of Pharmacy, University of North Carolina Medical Center, USA4Department of Neurology, University of North Carolina School of Medicine, USA

Abstract

Central nervous system (CNS) infection in neurocritically ill patients is associated with poor clinical outcomes. Therapeutic drug monitoring is recommended for dose optimization, which is routinely performed for antimicrobials such as vancomycin. The study objective was to quantify vancomycin pharmacokinetics in this population, and compare them with those predicted from population pharmacokinetic models.

Thirty adult critically ill patients with CNS infections admitted between May 1, 2010 - June 1, 2016 to UNC Medical Center’s Neurosciences ICU who received vancomycin for a CNS infection were included. The primary outcome was the difference between actual vs. predicted serum trough concentrations, elimination rate constant (ke), and elimination half-life (t1/2), evaluated using paired t-tests or Wilcoxon signed-rank tests at α = 0.05.

Two-thirds of the patients had developed meningitis or ventriculitis. The median admission estimated CrCl was 102.7mL/min. Median vancomycin regimens ranged from 16.6 - 21.3mg/kg/dose IV Q8H between first and second trough levels. The first vancomycin trough was sub-therapeutic for predicted and measured values. There were no differences between predicted vs. measured ke (at first level: 0.103 vs. 0.121 hr-1, p = 0.59; at second level: 0.107 vs. 0.112 hr-1, p = 0.71), or t1/2 (at first level: 6.7 vs. 5.7 hr, p = 0.57; at second level: 6.5 vs. 6.2 hr, p = 0.80).

In this study, no differences were observed between population-predicted and measured vancomycin pharmacokinetic parameters. Given the sub-therapeutic initial troughs and concern for early under-dosing in serious CNS infections, first-dose pharmacokinetic monitoring or obtaining measured CrCl may be beneficial.

ABBREVIATIONSActBW: Actual Body Weight; AdjBW: Adjusted Body

Weight; ARC: Augmented Renal Clearance; AUC: Area Under the Concentration-time Curve; CNS: Central Nervous System; CrCl: Creatinine Clearance; GCS: Glasgow Coma Scale Score; IBW: Ideal Body Weight; IQR: Interquartile Range; ke: Elimination Rate Constant; LOS: Length of Stay; MIC: Minimum Inhibitory Concentration; MRSA: Methicillin-Resistant Staphylococcus aureus; SCr: Serum Creatinine; SOFA: Sequential Organ Failure Assessment score; t1/2: Elimination Half-life; TBI: Traumatic Brain Injury; TTM: Targeted Temperature Management; Vd: Volume of Distribution

INTRODUCTIONIn neurocritically ill patients, central nervous system (CNS)

infections can exacerbate the underlying neurological insult, and therefore present a serious source of complications, morbidity,

and mortality. In a study of civilian patients who sustained penetrating gunshot wounds to the head, 25% of patients developed CNS infections. Of these patients, 12.5% developed meningitis, 6.25% developed brain abscess, 3.13% developed subdural empyemas, and 1.56% developed ventriculitis [1]. In a cohort study of 760 traumatic brain injury (TBI) patients, an association was observed between meningitis development and increased ICU length of stay (LOS), increased hospital LOS, and CNS device placement [2]. Despite advances in surgical prophylaxis, wound site care, and the use of antimicrobial prophylaxis post-injury in selected trauma subtypes, post-injury CNS infections remain of major concern [1,3]. CNS infections can lead to secondary neurologic injury, thereby hindering recovery.

CNS infections also present several challenges in their management. First, there are several mechanisms at the blood-brain and blood-CSF barriers that impede access of the drug to its site of action. Depending on the drug in question, these

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mechanisms may include active transport out of the CNS, presence of tight junctions between cells at the barrier, plasma protein binding, and intra-CNS metabolism [4]. The specific case of brain abscesses, which can be walled off the rest of the brain parenchyma, can raise additional barriers that antimicrobial agents need to penetrate in order to adequately treat the infection [5]. Using doses on the higher end of dosing ranges has been one strategy to attempt to improve CNS drug concentrations, but this can lead to dose-limiting toxicities.

Another concern for treating CNS infections is augmented renal clearance (ARC), in which there is abnormally high elimination of solute at the kidney. ARC is one of many physiologic derangements that critically ill patients may exhibit, occurring in as many as 65% of patients in a general ICU population [6], and 85% in a TBI population [7]. Udy et al., report the use of creatinine clearance (CrCl) thresholds of > 160mL/min/1.73m2 for men and > 150mL/min/1.73m2 for women to define ARC [8]. Though the time course and underlying pathophysiology behind this phenomenon may vary, ARC has major consequences on the disposition of renally cleared agents, which include many antimicrobial drugs. Faster elimination of antimicrobial agents may result in suboptimal drug concentrations, increasing the risk for not only treatment failure but also development of antimicrobial resistance. This has led to some investigators recommending therapeutic drug monitoring of beta-lactams and other renally cleared antimicrobials to facilitate patient-specific dosing [9-12].

One such renally-eliminated agent that is typically subjected to therapeutic drug monitoring is vancomycin, a common choice against methicillin-resistant Staphylococcus aureus (MRSA) infections. Pharmacodynamic efficacy of vancomycin is associated with its area under the concentration-time curve (AUC): Minimum Inhibitory Concentration (MIC) ratio. However, this ratio is not usually calculated in full in practice. Instead, serum trough concentrations of vancomycin are often measured at steady-state conditions to monitor for safety and efficacy of therapy, with a target range of 15-20mg/L for CNS infections. In select situations, serum peak or random levels may also be drawn. Population pharmacokinetic models have been derived to estimate the elimination rate constant (ke), half-life (t1/2), and volume of distribution (Vd) given a patient’s CrCl and weight, but these models were developed in a non-critically ill patient population [13].

The premise of the present study is to compare vancomycin pharmacokinetic parameters in a neurocritically ill cohort with concomitant CNS infection against predicted parameters using population pharmacokinetic models. We hypothesize the parameters measured from the patient cohort will significantly deviate from those predicted.

MATERIALS AND METHODSWe conducted a single-center retrospective study of

neurocritically ill patients and comorbid CNS infection. Adult patients admitted to the UNC Medical Center (UNCMC) Neurosciences Intensive Care Unit (NSICU) between May 1, 2010 - June 1, 2016 were included if they received vancomycin for either empiric or targeted therapy to treat a CNS infection,

Table 1: Baseline patient characteristics.

Variable

Neurocritically Ill Patients with CNS

Infections(n = 30)

Age (years) † 56 (46-64)Male gender * 12 (40)Height (in) † 67 (65-69.02)Actual Body Weight (kg) † 77.4 (67.4-93.8)Admission Serum Creatinine (mg/dL) † 0.69 (0.54-0.99)

Admission Creatinine Clearance (mL/min) † 102.66 (75.06-122.29)

Admission GCS Total † 14 (10-15)GCS 24 Hours Post-Admission † 14 (8-14)Admission SOFA † 2.5 (1-5)Primary Admission Diagnosis *

MeningitisWith ventriculoperitoneal shunt 6 (20)Other meningitis 3 (10)

CNS abscess (brain, spine) or empyema 6 (20)CNS tumor (brain, spine, pituitary) 5 (16.67)Subarachnoid hemorrhage 5 (16.67)Encephalopathy 2 (6.67)Subdural hematoma 1 (3.33)Acute ischemic stroke 1 (3.33)Traumatic brain injury 1 (3.33)

Selected Comorbidities *Hypertension 10 (33.33)Diabetes 1 (3.33)Congestive Heart Failure 1 (3.33)

CNS Interventions *External ventricular drain 13 (43.33)Surgical excision/aspiration 8 (26.67)Brain tumor resection 3 (10)Lumbar puncture 3 (10)Subdural hematoma evacuation 1 (3.33)Other 2 (6.67)

Infection Type *Meningitis 14 (46.67)Ventriculitis 6 (20)Shunt-Related Infection 4 (13.33)Abscess 3 (10)Other 3 (10)

Organism(s) Identified *Staphylococcus aureus 5 (16.67)Streptococcus pneumoniae 3 (10)Staphylococcus epidermidis 1 (3.33)Other 7 (23.33)Polymicrobial Infection 4 (13.33)No organism identified 10 (33.33)

* Number of patients (%). † Median (interquartile range). CNS: central nervous system; GCS: Glasgow Coma Scale; SOFA: Sequential Organ Failure Assessment.

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Table 2: Vancomycin regimen characteristics, fluid balance, and concomitant therapies at 1st and 2nd serum trough concentrations.

Variable First Vancomycin Trough(n = 30)

Second Vancomycin Trough(n = 20)

Dose (mg/kg actBW/dose) † 16.60 (14.78-20.27) 21.32 (16.12-26.83)

Dose (mg) † 1500 (1250-1500) 1500 (1250-2000)

Frequency (hours) † 8 (8-12) 8 (8-12)

Time between Vancomycin Trough and Preceding Dose (hours) † 8 (7.5-11) 7.5 (7-10.5)

Serum Creatinine at Trough (mg/dL) † 0.6 (0.49-0.80) 0.62 (0.52-0.79)

Creatinine Clearance at Trough (mL/min) † 119.3 (88.94-161.5) 123 (106.7-151.1)

GCS Total at Trough † 14.5 (13-15) 14.5 (13-15)

SOFA at Trough † 1 (0-4) 1 (0-2)

Ins/Outs (mL) †

Ins 24 Hours Pre-Trough 3290 (2395-4323) 2647 (1374-3763)

Outs 24 Hours Pre-Trough 2344 (1618-3775) 2484 (1175-3374)

Total Balance 24 Hours Pre-Trough 746 (436-1669) 790 (-413-1701)

Ins 48 Hours Pre-Trough 2728 (1446-4262) 2921 (1906-4185)

Outs 48 Hours Pre-Trough 2269 (1225-4546) 2193 (1163-4138)

Total Balance 48 Hours Pre-Trough 225 (-85-914) 822 (185-1812)

Total Outs 4740 (2850-7706) 5048 (3150-6673)

Total Balance 1030 (31-3995) 987 (-530-3812)

Duration of Vancomycin Treatment (days) † 9 (4-19) 14 (7-25.5)

Time to 1st Vancomycin Dose (days) † 3 (1-8) 2 (1-7)

Time to 1st Vancomycin Trough (days) † 5 (2-9) 5 (2-9)

Concomitant Antibiotics *

None 4 (13.33) 2 (10)

Cefepime 10 (33.33) 8 (40)

Meropenem 6 (20) 4 (20)

Ceftriaxone + Ampicillin 3 (10) 3 (15)

Ceftriaxone + Metronidazole 2 (6.67) 2 (10)

Cefepime + Metronidazole 2 (6.67) 1 (5)

Ceftriaxone 1 (3.33) --

Ampicillin/Sulbactam + Amphotericin B 1 (3.33) --

Fluconazole 1 (3.33) --

Vasopressor Use *

None 25 (83.33) 17 (85)

Norepinephrine 3 (10) 2 (10)

Norepinephrine + Phenylephrine 1 (3.33) 1 (5)

Norepinephrine + Vasopressin 1 (3.33) --

Diuretic Use *

None 25 (83.33) 18 (90)

Furosemide 5 (16.67) 2 (10)

† Median (interquartile range). * n (%). GCS: Glasgow Coma Scale; SOFA: Sequential Organ Failure Assessment.

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and had at least one steady-state vancomycin serum trough concentration recorded. Patients were excluded if they had renal impairment (on renal replacement therapy, had chronic kidney disease stage III-V, had SCr > 1.4 mg/dL, had history of nephrectomy), or were pregnant. Other patient data collected include: age, gender, height, weight, renal function (creatinine clearance [CrCl] and serum creatinine [SCr]), Glasgow Coma Scale (GCS) score, Sequential Organ Failure Assessment (SOFA) score, comorbidities (hypertension, diabetes mellitus, atrial fibrillation, and congestive heart failure), concomitant antibiotic use, fluid balance, CNS infection type, ICU LOS, and hospital LOS. Factors that might have affected vancomycin clearance were evaluated as well, including treatment with temperature modulation, vasopressors, and diuretics. Vancomycin-specific data collected include: vancomycin dose and frequency, duration of vancomycin therapy, time from admission to first vancomycin dose, and time between a trough-associated dose and the previous dose. Our institutional policy is to collect serum vancomycin troughs 30-60 minutes prior to the following dose. Serum vancomycin concentrations were quantified at the institution’s core laboratory using the VITROS 5600 platform and MicroTip® assay technology from Ortho Clinical Diagnostics (Raritan, NJ).

The primary outcomes were the differences in actual vancomycin pharmacokinetic parameters compared with predicted values in this patient population. Specifically, half-life (t1/2), elimination rate constant (ke), and volume of distribution (Vd) were evaluated. Predicted pharmacokinetic parameters were calculated using standard population pharmacokinetic equations [13]:

ke (predicted) = 0.00083* CrCl + 0.00443

Vd (predicted) = 0.7 L/kg actual body weight [actBW]

CrCl is the estimated creatinine clearance based on the Cockcroft-Gault equation [14], using measured (not rounded) SCr values. The weight used in the Cockcroft-Gault equation was determined as follows [15,16]:

1) If actBW ≤ ideal body weight (IBW) → use actBW

2) If IBW < actBW ≤ 125% of IBW → use IBW

3) If actBW > 125% of IBW → use adjusted body weight (adjBW)

IBW (Devine formula [17]) = (50kg if male | 45 kg if female) + 2.3 (height in inches – 60)

AdjBW = IBW + 0.4 (actBW – IBW)

The estimated serum vancomycin serum trough concentration was calculated using predicted pharmacokinetic parameters and compared to the actual measured serum vancomycin trough concentration. The following equation was used to calculate patient pharmacokinetic parameters based on measured steady-state serum vancomycin trough concentrations [18]:

ke (actual) = ln [(dose/Vd + Cmin) / Cmin] / τ,

where Vd is the volume of distribution, ke is the elimination rate constant, Cmin is the steady-state serum vancomycin trough concentration, and τ is the dosing interval. This equation operates under assumptions of steady-state bolus dosing in a

one-compartment model, to improve feasibility of calculations.

The study was approved by the University of North Carolina at Chapel Hill Institutional Review Board with a waiver of informed consent.

STATISTICAL ANALYSISBaseline patient characteristics and vancomycin regimen

characteristics were described using descriptive statistics. Categorical variables are represented as n (%) while continuous and ordinal variables are represented as median (interquartile range, IQR). Predicted pharmacokinetic parameters based on population data were compared to the actual pharmacokinetic parameters obtained from collected steady-state vancomycin serum trough concentrations using the Wilcoxon signed-rank test (or paired t-test when the paired differences were normally distributed, as determined by Shapiro-Wilk testing). A p value < 0.05 was considered statistically significant. All statistical analyses were carried out with Stata SE version 15.0 (StataCorp LLC, College Station, TX).

RESULTS AND DISCUSSIONThere were 32 patients with acute brain injury and CNS

infections identified during the study period. Two patients were missing vancomycin troughs, resulting in 30 patients included in the final analysis. Baseline patient characteristics are listed in Table 1. Most patients were female, with median age 56 years and admission GCS of 14. The median admission SCr was 0.69mg/dL, and the median estimated admission CrCl was 102.7mL/min. Of the comorbidities screened for in our patients, one-third of patients had hypertension, and none had atrial fibrillation. Meningitis and ventriculitis accounted for nearly two-thirds of infection types. External ventricular drains were placed in 43% of patients. Twenty-seven patients (90%) did not receive targeted temperature management (TTM). The median ICU LOS was 10 days (IQR 3-19 days), and the median hospital LOS was 17.5 days (IQR 9-26 days).

Vancomycin regimen characteristics, fluid balance, and concomitant therapies around the first and second (if drawn) trough concentrations are listed in Table 2. All 30 patients had at least one vancomycin trough level drawn, and 67% of patients had a second trough level drawn. There was a dose-by-weight increase from 16.6mg/kg every 8 hours to 21.3mg/kg every 8 hours between the first and second troughs. The SCr was 0.60-0.62mg/dL for each level, and the median estimated CrCls were 119.3-123mL/min. There appeared to be an overall net positive fluid balance in the 24-hour and 48-hour periods before each trough. The majority of patients received concomitant antimicrobial therapy, with 33%-40% receiving cefepime in addition to vancomycin. Most patients did not receive vasopressors or diuretics during the study period.

Vancomycin pharmacokinetic parameters were predicted for each patient using population pharmacokinetic equations. The comparison between the predicted and calculated (from actual measurements) pharmacokinetic parameters at both first and second serum troughs are listed in Table 3. Notably, both predicted and measured initial trough concentrations were subtherapeutic (13.2mg/L and 13.3mg/L, respectively).

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There were no differences between predicted vs. calculated values for elimination rate constant or elimination half-life at either the first or second trough level assessment.

Similar lack of difference in predicted vs. calculated vancomycin pharmacokinetic parameters were also found in prior studies. In a cohort of 166 acute brain injury patients, Oswalt et al., evaluated population vs. patient-specific t1/2 values for vancomycin. A difference in t1/2 of 0.31 hrs (p = 0.023) was identified, but this was deemed to be a small clinical difference [19]. Albanèse et al. evaluated vancomycin pharmacokinetics in serum and cerebrospinal fluid in 13 neurocritically ill patients (including TBI, subarachnoid hemorrhage, and stroke), some with and without bacterial meningitis, receiving continuously-infused vancomycin regimens. The Vd observed in that study is lower than that used in our study (0.2 L/kg vs. 0.7 L/kg, respectively); otherwise, our observed ke and t1/2 are comparable to what was observed in the Albanèse et al., study (the latter found ke = 0.100 hr-1 and t1/2 = 6.9 hr).

Of note, the median first vancomycin trough levels, both predicted and calculated values, in our study were sub therapeutic, which explains the dose-by-weight increase between the first and second troughs. Importantly, it suggests that the patients may have experienced subtherapeutic serum vancomycin troughs when dosed utilizing population pharmacokinetics (no patient-specific pharmacokinetic information available prior to first serum level). Potential reasons for these subtherapeutic levels include dosing strategy (intermittent vs. continuous infusion) and/or volume expansion during resuscitation. Continuous infusion regimens of vancomycin may be a dosing strategy to consider if traditional intermittent regimens are unable to maintain therapeutic concentrations. In a study of 125 post-operative ICU patients who received vancomycin, target serum trough concentrations were achieved earlier (day 3 vs. day 4, p = 0.022), and lower rates of subtherapeutic levels were observed (11% vs. 41%, p < 0.001) in patients on continuous infusion regimens compared with those who received intermittent dosing [20]. Furthermore, patients receiving fluid resuscitation (e.g. in polytrauma, sepsis, etc.) may experience unpredictable changes in volume of distribution [21-23].

ARC, which has been associated with significant increases in dosing requirements [24], might be another consideration to explain the subtherapeutic serum vancomycin troughs noted. ARC is typically a phenomenon observed in the acute or

hyperacute period after the initial physiological insult, and we did not collect renal function data on our cohort from prior to their initiation on vancomycin. Nevertheless, the true duration of ARC remains unknown [25], and our study therefore may partly serve as an exploratory study for ARC with vancomycin as the probe drug.

The findings of initially subtherapeutic serum vancomycin troughs are consistent with prior studies. Franco et al. reported an initial median trough of 10.04mcg/mL with an mean initial dose of 35.6mg/kg/day, in a cohort of 62 patients with CNS infections [26]. Shokouhi et al. reported an initial serum trough of 13.82mg/L with a maintenance regimen of 30mg/kg/day, in a cohort of 27 patients with acute community-acquired meningitis [27]. Oswalt et al. reported that 86.1% of their acute brain injury patients receiving vancomycin had initial troughs of < 15mcg/mL on their first vancomycin regimens [19]. Ultimately, vancomycin’s pharmacodynamic efficacy is typically characterized by its AUC: MIC ratio [28] (targeting AUC: MIC ≥ 400 for MRSA infections [29]), which is influenced by local vancomycin concentrations at the site of infection, as well as the MICs of the culprit bacteria. However, these measurements may not be readily available, and serum troughs targeting a goal range of 15-20mg/L have been used as a surrogate [29,30]. Given the importance of obtaining adequate antimicrobial drug exposure especially early on in the course of any infection, first-dose pharmacokinetics may be considered to optimize the patient’s regimen earlier in the treatment course.

There were limitations noted for this study. There was insufficient data available to calculate AUC: MIC values for vancomycin, which again is linked with the drug’s pharmacodynamic efficacy, in our retrospective study. It is a standard assumption that therapeutic vancomycin serum concentrations correlate with therapeutic concentrations at the site of action (e.g. brain parenchyma, meninges, or associated part of the CNS based on the infection type). However, it is well-known that this is not always true and that there may in fact be differences between even separate compartments of the CNS [4]. Moreover, predicted pharmacokinetic parameters were calculated using a one-compartment model, under assumptions of steady-state bolus dosing (instead of infusion dosing) to facilitate more tractable calculations. However, in situations of faster clearance or increased infusion duration, these equations start to deviate from steady-state infusion dosing equations.

Table 3: Vancomycin pharmacokinetic parameters, predicted (population pharmacokinetic equations) vs. calculated (based on actual measurements).First Vancomycin Serum Trough

Concentration (n = 30)Second Vancomycin Serum Trough

Concentration (n = 20)

Variable* PredictedValue

Measured/CalculatedValue p value Predicted

ValueMeasured/Calculated

Value p Value

Volume ofdistribution (L)

54.18 (47.18-65.66) -- -- 54.18

(49.04-64.40) -- --

Serum TroughConcentration

(mcg/mL)

13.16 (10.07-19.12) 13.25 (9.8-18.4) 0.345 17.64

(13.77-24.58) 19.15 (16.25-22) 0.879

Elimination RateConstant (hr-1)

0.103 (0.078-0.138) 0.121 (0.094-0.132) 0.591 0.107

(0.093-0.130) 0.112 (0.075-0.126) 0.714

Half-Life (hours) 6.70 (5.01-8.86) 5.74 (5.25-7.35) 0.573 6.51 (5.34-7.46) 6.17 (5.51-9.25) 0.799*Median (interquartile range)

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Volumes of distribution were computed using the population estimation equation of 0.7 L/kg. Vancomycin levels (either a peak or a random level on the same dosing curve) would have had to be collected to calculate actual volumes of distribution, which were not available given the retrospective nature of the study. The Cockcroft-Gault equation used to estimate CrCl was originally designed for use in a more ambulatory setting rather than in the critically ill, so the estimate it provides in this population may not be as precise [6]. Information on clinical, microbiological, or functional outcomes after the initial study period was not collected. The small sample size limits external validity, as well.

There are several avenues for further investigation. A larger, prospectively-designed study in which vancomycin peak and trough concentrations are drawn at steady-state would allow for more accurate calculation of actual patient-specific pharmacokinetic parameters. Similarly, using measured creatinine clearances (e.g. using an 8-hour urine collection method, extrapolated to 24 hours) would permit more accurate assessments of renal function, and may even be able to discern augmented renal clearance. The use of first-dose kinetics vs. measured creatinine clearances (in conjunction with population pharmacokinetic equations) early in the treatment course can be compared in their respective rates of achieving therapeutic trough levels, and/or AUC: MIC targets. Incorporation of other outcomes, including clinical cure, microbiological cure, and longer-term functional outcomes, would be instructive as well.

CONCLUSIONSIn conclusion, the predicted and calculated pharmacokinetic

parameters for vancomycin were comparable in an acute brain injury patient cohort with CNS infection. Initial serum vancomycin troughs were observed to be subtherapeutic.

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La MK, Ong A, Morbitzer K, Jordan DJ, Rhoney DH (2017) Vancomycin Pharmacokinetics in Neurocritically Ill Patients with Central Nervous System Infection. J Drug Des Res 4(7): 1061.

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