AAC Accepted Manuscript Posted Online 11 September 2017

Antimicrob. Agents Chemother. doi:10.1128/AAC.01249-17

Copyright © 2017 American Society for Microbiology. All Rights Reserved.

1 INFLUENCE OF MECHANICAL VENTILATION ON VANCOMYCIN PHARMACOKINETICS

2 ADMINISTERED BY CONTINUOUS INFUSION IN CRITICALLY ILL PATIENTS

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3 Susanna Edith Medellín-Garibay1, Silvia Romano-Moreno2#, Pilar Tejedor-Prado3, Noelia

4 Rubio-Álvaro3, Aida Rueda-Naharro3, Miguel Angel Blasco-Navalpotro3, Benito García3,

5 Emilia Barcia1

1
6 Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia,

7 Universidad Complutense de Madrid, Madrid, Spain; 2Departamento de Farmacia y

8 Tecnología de Medicamentos, Facultad de Ciencias Químicas, Universidad Autónoma de

9 San Luis Potosí, SLP, México; 3Hospital Universitario Severo Ochoa, Leganes, Spain.

10 Running head: Vancomycin Pharmacokinetics in Critically Ill Patients

11 *Address correspondence to Silvia Romano-Moreno, srm@uaslp.mx

12
13 ABSTRACT

14 Pathophysiological changes involved on drug disposition in critically ill patients, should be

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15 considered on the dosing optimization of vancomycin administered by continuous

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

18 model of vancomycin to determine clinical covariates, including mechanical ventilation,

19 that influence the wide variability of this antimicrobial. Vancomycin plasma

20 concentrations from 54 critically ill patients were simultaneously analyzed by population

21 pharmacokinetic approach. A nomogram was developed for dosing recommendations and

22 was internally evaluated throughout stochastic simulations. The vancomycin plasma

23 concentration versus time data were best described by a one-compartment open model

24 with exponential inter-individual variability associated to vancomycin clearance and

25 volume of distribution. Residual error followed a homoscedastic trend. Creatinine

26 clearance and body weight significantly dropped the objective function value, showing

27 their influence on vancomycin clearance and volume of distribution, respectively.

28 Characterization based on the presence of mechanical ventilation, demonstrated a

29 decreasing value of 20% on vancomycin clearance. External validation (n=18) was

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

32 population pharmacokinetic model was developed for the administration of vancomycin

33 by continuous infusion in critically ill patients, demonstrating the influence of creatinine

34 clearance and mechanical ventilation on vancomycin clearance, as well as the implications

35 on dosing rates to reach therapeutic range (20–30 mg/L).

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36 INTRODUCTION

37 Vancomycin is a glycopeptide antibiotic with wide bactericidal spectrum against large

38 GRAM positive bacteria, especially Staphylococcus, Streptococcus, and Enterococcus.

39 Among its indications, it is used to treat infections caused by methicillin-resistant

40 Staphylococcus aureus (MRSA), where vancomycin remains the treatment of choice even

41 over new alternatives (1, 2).

42 Time-dependent pharmacodynamics makes the effectiveness of this antibiotic dependent

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.

49 For this, monitoring of plasma concentrations at steady state, can be considered as an

50 alternative, and an accurate and practical parameter to increase effectiveness and limit

51 adverse effects (7).

52 Vancomycin has been related to nephrotoxicity, particularly associated to trough plasma

53 concentrations ≥ 15 mg/L, duration of therapy ≥ 7 days, previous renal insufficiency, and

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54 concomitant administration of nephrotoxic agents (8-10).

55 Therapeutic drug monitoring (TDM) is presented as an strategy to reduce nephrotoxicity,

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

64 plasma concentrations to rapidly achieve adequate plasma concentrations (12, 15-17).

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

67 on increased volume of distribution as in case of generalized edema, ascites, and

68 hypoalbuminemia among others such as mechanical ventilation; as well as changes in

69 hepatic and renal clearance (18-21). These aspects are especially important in critically ill

70 patients as improper treatment either by incorrect dosage or wrong choice of the

71 administration procedure, have been frequently associated with treatment failure, poor

72 prognosis and development of multidrug resistance.

73 The aim of this study is to develop a population pharmacokinetic model of vancomycin

74 administrated by continuous infusion to critically ill patients admitted to ICUs, to

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75 determine the factors that influence its variability and to improve the dosage in this

76 population to reduce the risk of both, over- and sub-therapeutic doses.

77 MATERIALS AND METHODS

78 A retrospective study was performed including adult patients from the ICU with proven or

79 suspected infection receiving vancomycin by continuous intravenous infusion and routine

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

82 from pregnant women, patients undergoing hemofiltration, and patients with

83 hematological malignancies, burns or cystic fibrosis were excluded from the current study.

84 Clinical information regarding vancomycin administration was retrieved from each

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

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96 such as furosemide, non-steroidal anti-inflammatory drugs (NSAIDs), catecholamine and

97 aminoglycosides was included as categorical data.

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.

102 Vancomycin assay

103 Vancomycin serum concentrations were quantified by ‘Roche/Hitachi Cobas c’ assay

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).

108 Development of the population pharmacokinetic model

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

111 with Perl-speaks-NONMEM (PsN) 3.5.3 (23). Compartmental pharmacokinetic models

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

115 (http://www.pirana-software.com/, open source, modeling workbench for NONMEM, PsN

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116 and Xpose) (24, 25). The first-order conditional estimation method with interaction (FOCE-

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

132 co-medication. Preliminary selection of covariates was performed by the Stepwise

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

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137 function value (OFV) were considered at significance level of P<0.05 for forward addition

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

140 referenced models were used to evaluate the covariates.

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

146 physiologically reasonable results.

147 Validation of the population pharmacokinetic model

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

151 population pharmacokinetic model was evaluated by fixing pharmacokinetic parameters,

152 as well as IIV and RV, and setting dependent value to zero on each time where it was

153 expected to estimate plasma concentrations. Vancomycin serum concentrations from

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,

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158 29).

159 Dosing recommendations

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

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178 present in 50% of them; respiratory infections and pneumonia (24%). Twenty-two percent

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

191 concentrations vs sampling times for the population study group.

192 Population pharmacokinetic model

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.

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198 Continuous covariates that showed significant influence and therefore, were included to

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

204 bootstrapping, allowed to visualize that influence of catecholamine concomitant

205 administration on vancomycin CL was insufficiently characterized, then this covariate was

206 also eliminated from this preliminary final model.

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.

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219 External validation

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

228 pharmacokinetic model, respectively.

229 Dosing recommendations

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 mgh/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

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239 dosing considerations.

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

243 convenience of administrating vancomycin as continuous infusion, especially for the

244 critically ill patient that requires achieving target concentrations faster and with less

245 variability (13, 30, 31).

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

254 considering the influence of mechanical ventilation on vancomycin pharmacokinetics and

255 consequently, the implication on infusion rates to maintain target steady-state

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

258 regimens (34).

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259 Considering that Vd is higher than the one reported for non-critically ill patients but lower

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

271 previously suggested (14, 37, 38).

272 Several authors have studied vancomycin pharmacokinetics administered by continuous

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

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280 well as lower renal blood flow, glomerular filtration rate and urine flow, has been already

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

286 associated with vancomycin underexposure (27).

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

295 is administered by continuous infusion (44, 45).

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

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301 populations must be done with caution. Extreme values of CRCL should be carefully

302 assessed, since most of the patients included in the current population exhibited CRCL

303 values ranging from 50 to 150 mL/min.

304 Additionally, further studies to evaluate safety, effectiveness and toxicity of this bordering

305 vancomycin concentrations should be performed to explore risk-benefit balance of

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

319 validation of dosing nomogram proposed should be performed.

320 ACKNOWLEDGMENTS

321 The authors acknowledge the assistance of the pharmacists, analytical technicians, nurses

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322 and medical staff of the Hospital Universitario Severo Ochoa (Leganés, Spain) for their

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-

325 Garibay for Postdoctoral fellowship (Register 237235).

326 All the authors declare that they have no conflict of interest.

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462
463 FIGURES LEGENDS

464 Fig 1. Vancomycin plasma concentrations vs sampling times (n=641) for the population

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465 study group (n=54). [Dash lines are the expected range of plateau plasma concentrations

466 for vancomycin administered by continuous infusion to critically ill patients].

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

470 administrated by continuous infusion (n=54).

471 Figure 3. Distribution of the plateau plasma concentration of vancomycin administered by

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).

476 Figure 4. Nomogram proposed for vancomycin administered by continuous infusion to

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

validation of the pharmacokinetic model of vancomycin administered by continuous

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infusion to critically ill patients.

Variable Population Validation group

group (n=54) (n=18)
Sex (male) 70% 61%

Age (years) 65.0 ± 12.3 69 ± 12.5

TBW (kg) 75.0 ± 20.1 74.9 ± 15.4

BMI (kg/m2) 28.5 ± 7.0 28.1 ± 5.0

CRCL (mL/min) 106.3 ± 64.5 134.7 ± 91.0

Urea (mg/dL) 61.4 ± 38.8 65.3 ± 37.4

Uric acid (g/dL) 4.6 ± 2.5 3.7 ± 1.8

Total protein (g/dL) 5.0 ± 0.8 5.3 ± 0.7

Albumin (g/dL) 2.7 ± 1.5 2.8 ± 0.7

Total bilirubin (g/dL) 0.99 ± 1.2 0.7 ± 0.5

AST (U/L) 51.1 ± 60.1 53.2 ± 55.7

ALT (U/L) 43.5 ± 38.3 33.6 ± 27.7

APACHE II Score 18 (9 – 25) 21 (11 – 44)

Mechanical ventilation 74% 78%

Vancomycin rate (mg/h) 62 ± 30 69 ± 32

 Table 2. Final population pharmacokinetic model and internal validation for vancomycin

administered by continuous infusion to critically ill patients (n = 54).

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BOOTSTRAP (n=1000)
PHARMACOKINETIC MODEL PARAMETER MEAN (RSE)
MEDIAN PERCENTIL

2.5th 97.5th

CL L/h = Θ1 × [ CRCL/ ^Θ3] Θ1 2.86 (6%) 2.87 2.54 3.33

*If mechanical ventilation: Θ3 0.75 (14%) 0.75 0.57 0.99

CL L/h = Θ1 × [ CRCL/ ^Θ3] × Θ4 Θ4 0.80 (8%) 0.79 0.67 0.93

Vd L/kg = Θ2 × TBW Θ2 1.03 (8%) 1.02 0.87 1.22

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.

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Prediction Predicted MPE APE RMSE
method concentration Mean (95% CI) Mean (95% CI) (mg/L)
Mean ± SD (mg/L) (mg/L)
(mg/L)
Base model 24.4 ± 11.6 3.2 (1.7, 4.6) 9.3 (8.4, 10.2) 11.7

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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