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Influence of Mechanical Ventilation On Vancomycin Pharmacokinetics Administered by Continuous Infusion in Critically Ill Patients
Influence of Mechanical Ventilation On Vancomycin Pharmacokinetics Administered by Continuous Infusion in Critically Ill Patients
Influence of Mechanical Ventilation On Vancomycin Pharmacokinetics Administered by Continuous Infusion in Critically Ill Patients
5 Emilia Barcia1
1
6 Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia,
9 San Luis Potosí, SLP, México; 3Hospital Universitario Severo Ochoa, Leganes, Spain.
12
13 ABSTRACT
16 infusion, and certain strategies must be applied to reach therapeutic targets on the first
17 day of treatment. The aim of this study was to develop a population pharmacokinetic
23 concentration versus time data were best described by a one-compartment open model
26 clearance and body weight significantly dropped the objective function value, showing
30 performed to evaluate the prediction ability of the model with median bias and precision
31 values of 0.7 mg/L (95%CI -0.4, 1.7) and 5.9 mg/L (95%CI 5.4, 6.4), respectively. A
40 Staphylococcus aureus (MRSA), where vancomycin remains the treatment of choice even
43 on the time that plasmatic concentrations are above the Minimal Inhibitory Concentration
44 (MIC) of the causative organism of infection. The area under the concentration versus
45 time curve for 24 h (AUC) over MIC (AUC/MIC) is the parameter that better correlates
46 efficiency of vancomycin (3, 4). Values of AUC ≥400 mg·h/L, assuming that MIC is ≤1 mg/L,
47 have been associated with clinical improvement and shorter times for microbiological
48 eradication (5, 6). However, in clinical practice it can be complicated to determine AUC.
50 alternative, and an accurate and practical parameter to increase effectiveness and limit
56 being recommended primarily for patients who require long-duration treatments, high
57 doses to treat infections in tissues where vancomycin has low penetration or patients with
58 concomitant treatment with other nephrotoxic drugs (3, 4, 11). The use of continuous
59 infusion to reach plateau concentrations of 20–30 mg/L has been previously proposed to
60 increase vancomycin therapeutic effect and to avoid the risk of nephrotoxicity (6, 9, 12-
61 14). Despite differences on effectiveness has not been proven, the clinical application of
62 vancomycin by continuous infusion has been increasing due to ease of handling and lower
63 costs than intermittent infusion; as well as less sampling for TDM, with less variability in
65 In critically ill patients admitted to Intensive Care Units (ICUs) pathophysiological changes
66 with effect on vancomycin pharmacokinetics occur. These changes are mainly dependent
69 hepatic and renal clearance (18-21). These aspects are especially important in critically ill
71 administration procedure, have been frequently associated with treatment failure, poor
78 A retrospective study was performed including adult patients from the ICU with proven or
80 TDM. Data collection was performed between 2010 and 2015, following ethical and
81 confidential procedures of the Hospital Universitario Severo Ochoa (Leganés, Spain). Data
83 hematological malignancies, burns or cystic fibrosis were excluded from the current study.
85 patient’s medical record (start of infusion, rate and/or bolus administration), as well as
86 data from TDM (serum sampling date and time, as well as assay concentration). Age
87 (years), sex, total body weight (TBW; kilograms), height (centimeters) and serum
88 creatinine concentration (milligrams per deciliter) data were also retrieved from each
89 patient’s medical record. These data were used to estimate body mass index (BMI;
90 kilograms per meter squared; calculated as TBW divided by height in meters squared),
91 body surface area (BSA; meters squared; calculated as [(TBW×height)/3600]2) and total
92 creatinine clearance (CRCL; milliliters per minute per 1.73 m2) based on the Cockcroft–
93 Gault equation (22). Clinical data such as disease severity score on admission (as assessed
94 by the APACHE II score), concentrations of urea, uric acid, total proteins, albumin, total
95 bilirubin, ALT and AST were also recorded. Information about concomitant medication
98 The total population assayed was divided into two groups: one group, composed of 54
99 patients, was used to build the population pharmacokinetic model (population study
100 group); and the other one, composed of 18 patients, was used for external validation
101 (validation study group). Patients were randomly assigned to each group.
104 system (Hoffmann-La Roche, Basel, Switzerland) based on immunoassay following the
105 manufacturer’s procedure. The quantification limit was 1.7 mg/L and the intra- and inter-
106 assay coefficients of variation (CVs) were <5% over the entire calibration range (1.7–80
107 mg/L).
109 The population pharmacokinetic model was built using nonlinear mixed-effects modeling
110 via NONMEM software v7.3 (Icon Development Solutions, Dublin, Ireland) in conjunction
112 were coded using ADVAN1 and ADVAN3 subroutines in NONMEM. Data exploration and
113 graphics were handled using Xpose 4.3.5 embedded in R 3.1.0 (http://cran.r-project.org/,
114 open-source, S-based statistical software) and were integrated through Pirana Software
117 I) was used to estimate the pharmacokinetic parameters. Models were fitted to raw
118 concentration-time data, and shrinkage on both eta and epsilon was reported. The
119 precision of the parameter was estimated using the covariance step. Visual inspections of
120 the vancomycin plasma concentration versus time profiles and the Akaike Information
121 Criterion (AIC), were evaluated to investigate the base model (26).
122 Exponential inter-individual variability (IIV) was tested on all pharmacokinetic parameters
123 for which estimation of variability was plausible; the residual variability (RV) was modeled
124 as an additive error model. Full-block omega structure on the base model was considered,
125 followed by inspection of the correlations among the IIVs for the development of omega
126 structure.
127 Followed to base model selection, a total of 12 covariates were evaluated in a stepwise
128 forward covariates inclusion procedure but only significant covariates were retained in a
129 full model to characterize vancomycin PK parameters through backward elimination (26).
130 The continuous covariates tested were age, TBW, BMI, BSA, serum creatinine, CRCL and
131 glucose. The categorical covariates evaluated were gender, mechanical ventilation, and
133 Generalized Additive Model (GAM) analysis (24, 25). Augmented renal clearance was
134 evaluated as categorical covariate when CRCL > 130 mg/L, since It has been considered a
135 clinically relevant phenomenon in critically ill patients (27). The covariate selection for the
136 final model was guided using likelihood ratio tests. Changes in the minimum objective
138 of covariates (ΔOFV >3.84) and P <0.001 for backward elimination of covariates (ΔOFV
139 >10.83). Diagnostic plots and comparisons of changes in the minimum OFV between the
141 Continuous covariate effects were introduced into the population model using a variety of
142 functions, including linear, power or exponential; covariates were also centered to the
143 median value in the database (allometric function) (26). Discrete covariates were usually
144 set to 0 for the reference classification and introduced as described by Mould D.R. and
145 Upton R.N. (2013) (26). Parameterization of the covariate models must derive in
148 The final model was internally validated by bootstrapping to evaluate stability of the
149 parameters distribution with the covariates included; external validation was also
150 performed with an alternate group of patients. The predictive performance of the final
152 as well as IIV and RV, and setting dependent value to zero on each time where it was
154 routine TDM of the validation group were compared to their predicted values to estimate
155 the precision of the population model built. The bias fit was evaluated by means of the
156 mean prediction error (MPE). Precision was estimated by means of the absolute
157 prediction error (APE), and the root-mean-squared of the prediction error (RMSPE) (28,
160 A nomogram was developed considering that plateau plasma concentrations at steady
161 state (Cpss) are recommended to be between 20 – 30 mg/L. The rate (mg/h) was
162 calculated based on the desired Cpss (25 mg/L as average) divided by vancomycin CL (Rate
163 = Cpss × CL), considering the covariates included in the final population pharmacokinetic
164 model.
165 Stochastic simulations were performed to predict vancomycin concentrations with the
166 different infusion rates proposed. A range of CRCL from 40 to 200 mL/min/1.73 m2 was
167 evaluated with the different doses of vancomycin estimated as multiples of 8 mg/h,
168 considering 2 grams of vancomycin diluted in 250 ml of saline solution (C0 = 8 mg/L). The
169 simulations were performed with 1000 patients by means of the final population
170 pharmacokinetic model using the fixed parameter estimates, IIV and RV. Individual
171 concentrations predicted at steady state were obtained for each simulated patient and
172 the AUC for 24 hours (AUC24) was calculated from Cpss*24.
173 RESULTS
174 A total of 874 vancomycin plasma concentration were included for the development of
175 the current study. Data from a total of 72 patients was retrieved; 54 of them were used
176 for model development and 18 for external validation; patients’ characteristics are
177 summarized on Table 1. The most common diagnoses were sepsis (44%), with septic shock
179 of the patients developed acute respiratory destress syndrome and 6% underwent
180 multiorgan failure. APACHE II score ranged from 9 to 25 and mechanical ventilation was
181 implemented in 74% of patients; most common co-medication was NSAIDs, furosemide
182 and catecholamine for 20%, 48% and 44% of patients, respectively. Renal function was
183 highly variable, based on CRCL, fluctuating from 27.2 to 271.6 mL/min/1.73 m2; being over
184 130 mL/min/1.73 m2 in 29% of the patients and 28% showed CRCL <60 mL/min/1.73 m2.
185 Regarding vancomycin dosage in population group, most of the patients (80%) received a
186 mean loading dose of 12 ± 5 mg/kg of TBW, followed by continuous infusion at a mean
187 rate of 60 mg/h (from 14 – 180 mg/h). TDM was performed at least once, with an average
188 of 8 determinations per patient (range 1 – 36). Vancomycin plasma concentrations ranged
189 from 1.7 – 51.1 mg/L (22 ± 6 mg/L); 57% were within the desired range (20 – 30 mg/L),
190 and 35% were <20 mg/L. Figure 1 shows the distribution of vancomycin plasma
193 Vancomycin plasma concentrations from critically ill patients after continuous intravenous
194 infusion are best described by a one-compartment open model with exponential IIV
195 associated to CL and Vd; RV was fitted to homoscedastic model (additive) for the full
196 range of concentrations. This base structural model estimated initial values of CL (2.7 L/h)
197 and Vd (76.5 L), with IIV of 50% and 61%, respectively; and a RV of ±5 mg/L.
199 this base model were CRCL on vancomycin CL, and TBW on Vd. Sequentially, univariate
200 analysis including each categorical covariate was performed; mechanical ventilation, as
201 well as the co-administration of furosemide and catecholamine provided significant drop
202 in the OFV, when included on vancomycin CL. Nevertheless, on backward elimination,
203 furosemide did not remain as significant covariate. Distributions obtained from
205 administration on vancomycin CL was insufficiently characterized, then this covariate was
207 Finally, the full model included CRCL as power-centered relationship on vancomycin CL as
208 well as mechanical ventilation, calculating a distinct parameter for these patients, being
209 20% lower for those sorted with this characteristic. TBW was included as direct covariate
210 on Vd. The parameters estimate for this final model are shown in Table 2, as well as the
211 results from bootstrapping the original dataset (n=1000), which confirms the stability and
212 precision of the pharmacokinetic parameters since all the final estimates are close to the
213 median and within non-parametric 95% CI. The IIV associated to CL and Vd was reduced to
214 28.4% and 49%, respectively, as well as RV was reduced by 14%, when compared to base
215 model variability. The shrinkage values were 5% for IIV associated to CL, 11% for IIV
216 associated to Vd, and 7% for RV. Representative mean plot of goodness of fit is shown in
217 Figure 2a. Conditional weighted residuals (CWRES) are randomly spread around zero-line
218 without trends observed for the final population model, as depicted in Figure 2b.
220 External evaluation was performed with 233 vancomycin plasma concentrations which
221 ranged from 6.4 to 40.6 mg/L and were retrieved from patients with similar characteristics
222 to the population study group (Table 1). The prediction ability of the final model was
223 compared with the base structural model. The mean values and 95% CI of the bias and
224 imprecision are depicted in Table 3. Lower values were obtained for the final model and
225 the MPE is well distributed around zero. Based on a mean plasma concentration of 21.3
226 mg/L measured for this group, the average error diminished from 43.7% to 27.7%, when
227 comparing concentrations predicted with the base versus the final population
230 Based on CRCL and mechanical ventilation, stochastic simulation based the final
231 population model were performed as shown in Figure 3 to internally evaluate the
232 nomogram developed for initial dosing recommendations as stated on Methods section
233 (Figure 4). Different infusion rates have been proven to reach concentrations between 20
234 – 30 mg/L and the AUC0-24 >400 mgh/L for at least 50% of the simulations. As the Vd
235 estimated is 1.03 L/kg, a loading dose of 25 mg/kg administered over 120 minutes has
236 been considered for stochastic simulations, to reach the steady state earlier. Dashed lines
237 represent the infusion rates for patients undergoing mechanical ventilation, since
238 vancomycin CL is 20% lower for these patients and its influence has been proven for
240 DISCUSSION
241 A population pharmacokinetic model has been successfully developed for vancomycin
242 administrated by continuous infusion to critically ill patients. It is well known the
244 critically ill patient that requires achieving target concentrations faster and with less
246 One-compartment open model was the best fit, supported by sparse data concentrations
247 retrieved; two-compartment modeling could not be characterized as expected. This fact is
248 in accordance with Roberts et al. (2011), who also proposed a one-compartment open
249 model for patients with similar characteristics and the influence of CRCL and TWB on CL
250 and Vd, respectively (19). However, other authors, Revilla, et al. (2010) and LLopis-Salvia
251 P. et al. (2006), developed two-compartment open modeling for critically ill patients
252 receiving vancomycin as intermittent infusion and demonstrating the influence of the
253 same covariates on fixed parameters (32, 33). On the other hand, this is the first work
256 concentrations between 20 and 30 mg/L, and strengthens the heterogeneous attributes
257 of critically ill patients that enhances the need for individualization of antimicrobial
260 than that for septic patients (19, 35), categorization according to disease or severity was
261 also proved; nevertheless, no differences were found but the value obtained for Vd shows
262 the need of higher doses to avoid clinical failure due to suboptimal exposure of
263 vancomycin at the site of infection, however being lower than those proposed for other
264 populations. Hydrophilic drugs, such as vancomycin, remain in the plasma water volume;
265 nevertheless, this relative Vd increases due to capillary leak syndrome and might be
266 enhanced when fluids are infused, as part of the resuscitation intervention, commonly
267 applied to critically ill patients (36). Moreover, hypoperfusion of peripheral tissues is a
268 common manifestation in many critically ill patients, limiting the distribution of
269 hydrophilic drugs to non-central tissues (36). Actually, on clinical practice, lower loading
270 doses were initially administered to this population, comparing to standard doses
273 infusion to different populations with all of them demonstrating high variability in the case
274 of critically ill patients. In fact, vancomycin CL for the current study is slower than the one
275 reported by Roberts J.A. et al. (2010), but similar to that given by Cristalini S. et al. (2016)
276 (14, 19); both studies being performed after continuous administration of vancomycin, as
277 the current one. Furthermore, decreasing CL of vancomycin has been demonstrated for
278 patients ongoing mechanical ventilation. The influence of mechanical ventilation on
279 decreased drug clearance due to hemodynamic changes such as minor cardiac output, as
281 discussed (36, 39). Moreover, it has been previously proved that vancomycin distributes to
282 the epithelium lining fluid, which is the one that lines the small distal airways, with
283 mechanical ventilation being able to alter the alveolar-capillary membrane permeability to
284 proteins (40, 41). Conversely, Minkute et al. (2013), consider mechanical ventilation as a
285 risk factor for augmented renal clearance for critically ill patients, and demonstrated being
287 Target steady-state levels have been proposed based on pharmacodynamic studies and
288 varies from 15 to 30 mg/L; bacterial killing and suppressing vancomycin resistance are
289 based on the AUC/MIC ratio with values of 480 when it is administered by continuous
290 infusion which is reached with steady-state concentration of 20 mg/L, when vancomycin
291 pathogen MIC is 1 mg/L, and it has been suggested to rise this target concentration to 25
292 mg/L given increasing MIC in clinical isolates of S. aureus (42, 43). This target
293 concentrations must be taken with caution since it has been reported that steady state
294 concentrations over 30 mg/L are related to higher risk of nephrotoxicity when vancomycin
296 The proposed dosing rates to optimize this therapy were designed trying to achieve PK/PD
297 targets on the first 24 hours, considering as most of the previous studies, total body
298 weight and CRCL, but also considering the contribution of mechanical ventilation on
299 vancomycin CL. One of the main limitations of the current study is that the proposed
300 nomogram has not been prospectively validated yet and extrapolation to different
302 assessed, since most of the patients included in the current population exhibited CRCL
304 Additionally, further studies to evaluate safety, effectiveness and toxicity of this bordering
306 reaching earlier target concentrations and being closer of toxic ones. The population
307 pharmacokinetic model developed ensures better dose adjustments through Bayesian
308 procedures for drug monitoring. In fact, external validation proves the predictive
309 performance of the final pharmacokinetic model and the stochastic simulations evaluated,
310 thereby allowing to propose a reliable dosing nomogram, that results plausible for clinical
311 practice.
312 CONCLUSION
313 A population pharmacokinetic model has been developed for the administration of
314 vancomycin by continuous infusion in critically ill patients. It has been demonstrated the
315 influence of CRCL and mechanical ventilation on vancomycin CL, and the consequence on
316 dosing rates for this special population. The predictive performance of the final
317 pharmacokinetic model was evaluated by external validation. Loading doses and TDM are
318 strategies that also must be still considered for dosing optimization. Further prospectively
321 The authors acknowledge the assistance of the pharmacists, analytical technicians, nurses
323 contributions to the present study; as well as the support given by the Technological
324 Research Council of Science and Technology (CONACYT) from Mexico to S.E. Medellín-
326 All the authors declare that they have no conflict of interest.
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463 FIGURES LEGENDS
464 Fig 1. Vancomycin plasma concentrations vs sampling times (n=641) for the population
467 Figure 2. Scatter plots of goodness of fit of (a) PRED vs DV vancomycin concentrations
468 (including the identity line) and (c) CWRES vs TAD (including the zero line) for the final
469 one-compartment open model for critically ill patients receiving vancomycin
472 continuous intravenous infusion (76 mg/h) simulated for patients without (green) or with
473 mechanical ventilation (blue) and different renal function (n = 1000) based on final
474 population pharmacokinetic model. Therapeutic range is between 20 and 30 mg/L (red
475 lines).
477 critically ill patients and per creatinine clearance and mechanical ventilation [dashed line].
Table 1. Clinical characteristics of the patients included for the development and
2.5th 97.5th
28.4 (12%)
% IIV associated to CL ω2CL 27.6 21.4 36.1
[5%]
49.1 (10%)
% IIV associated to Vd ω2Vd 48.4 36.7 57.5
[11%]
4.3 (18%)
Residual variability (mg/L) σ 4.3 3.6 5.2
[7%]
[Shrinkage]
Table 3. Mean prediction errors ( standard deviation) and 95% CI estimated for the
validation group with the base and final one-compartment open model.
Final model 21.9 ± 7.9 0.7 (-0.4, 1.7) 5.9 (5.4, 6.4) 7.1
MPE (mean prediction error), APE (absolute prediction error), RMSE (root-mean-squared prediction error).
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