Plasma and tissue concentrations of 2 g prophylactic cefazolin prior to lower extremity surgery.

Surgical site infections (SSIs) are among the most clinically relevant complications and the use of prophylactic cefazolin is common practice. However, the knowledge about the pharmacological aspects of prophylactic cefazolin in the lower extremities remains limited. In this prospective cohort, a sub-study of the WIFI-2 randomized controlled trial, adults between 18 and 75 years of age who were scheduled for implant removal below the level of the knee and randomized for cefazolin, was included. A maximum of two venous plasma, target-site plasma, and target-site tissue samples were taken during surgery. The primary outcomes were the cefazolin concentrations in venous plasma, target-site plasma, and target-site tissue. A total of 27 patients [median (interquartile range) age, 42 (29-59) years; 17 (63%) male] with 138 samples were included in the study. A minimum of 6 weeks follow-up was available for all patients. The mean (SD) venous plasma, target-site plasma, and target-site tissue concentrations were 36 (13) µg/mL, 29 (13) µg/mL, and 28 (13) µg/g, respectively, and the cefazolin concentrations between the different locations of surgery did not differ significantly in both target-site plasma and target-site tissue (P = 0.822 and P = 0.840). In conclusion, 2 g of prophylactic cefazolin demonstrates adequacy in maintaining coverage for a duration of at least 80 minutes of surgery below the level of the knee, significantly surpassing the MIC90 required to combat the most prevalent microorganisms. This study represents the first of its kind to assess cefazolin concentrations in the lower extremities by examining both plasma and tissue samples in this magnitude.

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia.

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T>MIC) (for efficacy purposes and 100% T>4×MIC and 100% T>5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T>MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T>MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T>4×MIC and 100% T>5×MIC are desired.

Population Pharmacokinetics of Ganciclovir in Critically Ill Patients.

BACKGROUND: The pharmacokinetic (PK) data of ganciclovir (GCV), a first-line antiviral treatment for cytomegalovirus infections, in critically ill patients are limited. This study aimed at characterizing GCV population PK and interindividual variability (IIV) in intensive care unit (ICU) patients. Secondary objectives were to identify patient characteristics responsible for IIV and simulate GCV exposure for different dosing regimens. METHOD: In this retrospective observational study, clinical data and serum GCV levels were collected from ICU patients on intravenous GCV. PK modeling, covariate analyses, and explorative Monte Carlo dosing simulations (MCS) were performed using nonlinear mixed-effects modeling. Bootstrap and visual predictive checks were used to determine model adequacy. RESULTS: In total, 128 GCV measurements were obtained from 34 patients. GCV PK conformed to a 1-compartment model with first-order elimination. After multivariate analyses, only the estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (P < 0.001) was included as a covariate. In the final model, the estimated clearance (CL) and volume of distribution (V1) were 2.3 L/h and 42 L, respectively, for a patient with the median CKD-EPI of the population (65 mL/min per 1.73 m). The association between CKD-EPI and CL decreased the residual variability from 0.56 to 0.43 and V1-IIV from 114% to 80%, whereas CL-IIV changed from 43% to 47%. MCS revealed that a substantial number of patients may not achieve the GCV PK/pharmacodynamic target trough level (>1.5 mg/L) when administering the label-recommended dose reductions for patients with CKD-EPI <50 mL/min. CONCLUSIONS: A large IIV was observed in GCV PK among ICU patients. CKD-EPI could partially explain the IIV, although a large part of the variability remains unclear. MCS suggested that recommended dose reductions for CKD-EPI <50 mL/min may lead to subtherapeutic plasma GCV levels in these patients.

Correction to: Neonatal bacterial meningitis versus ventriculitis: a cohort-based overview of clinical characteristics, microbiology and imaging.

This article originally published with all author names incorrectly listed. All author names have now been transposed and appear correctly above.

Neonatal bacterial meningitis versus ventriculitis: a cohort-based overview of clinical characteristics, microbiology and imaging.

Central nervous system (CNS) infections are potentially life threatening in neonates and can lead to the ill-defined diagnosis of ventriculitis. With this study we aimed to explore and describe ventriculitis regarding clinical, microbiological and ultrasonographic characteristics. We performed a retrospective cohort study including all neonates with a culture-proven CNS infection admitted to our tertiary NICU over a 12-year period (2004-2016). For each case clinical data was gathered, and three timed cranial ultrasounds were anonymized and retrospectively reviewed and assessed for signs of ventriculitis. Forty-five patients were included with 9 (20%) diagnosed with ventriculitis. Mortality in both ventriculitis and non-ventriculitis cases was one-third. Patients with pre-existing conditions as post-haemorrhagic hydrocephalus are at risk of developing ventriculitis. Most common pathogens were gram negative bacteria (68.9%). Ultrasonographic signs of ventriculitis developed over time, and interrater agreement was substantial.Conclusion: Neonatal ventriculitis is a serious entity in the continuum of meningitis. Early and correct diagnoses of ventriculitis are both important because of possible persisting or newly developing hydrocephalus or seizures. Sequential imaging should be performed. What is Known: • CNS infections in neonates lead to high mortality and morbidity. • Ventriculitis is a severe complication of meningitis. What is New: • High morbidity; the majority of ventriculitis patients have pre-existing PHVD and develop seizures and hydrocephalus. • Interrater agreement is good; bedside CUS is a useful tool for reaching a sustainable diagnosis of ventriculitis.

Population Pharmacokinetics and Dosing Considerations for Gentamicin in Newborns with Suspected or Proven Sepsis Caused by Gram-Negative Bacteria.

The aim of this study was to describe the population pharmacokinetics (PK) of gentamicin in neonates with suspected or proven Gram-negative sepsis and determine the optimal dosage regimen in relation to the bacterial MICs found in this population. Data were prospectively collected between October 2012 and January 2013 in the Neonatal Intensive Care Unit (NICU) at the Academic Medical Center (AMC), Amsterdam, The Netherlands. A single nonlinear mixed-effects regression analysis (NONMEM) was performed to describe the population PK of gentamicin. Dosage regimens based upon gestational age (GA) were generated using Monte Carlo simulations with the final model. Target values were based on the MIC distribution in our patient population. In total, 136 gentamicin concentrations from 65 (pre)term neonates were included. The PK was best described by an allometric 2-compartment model with postmenstrual age (PMA) as a covariate on clearance (Cl). The MIC distribution (median, 0.75 [range, 0.5 to 1.5] mg/liter) justified a gentamicin target peak concentration of 8 to 12 mg/liter. This study describes the PK of gentamicin in (pre)term neonates. Dosage regimens of 5 mg/kg of body weight every 48 h, 5 mg/kg every 36 h, and 5 mg/kg every 24 h for patients with GAs of <37 weeks, 37 to 40 weeks, and ≥40 weeks, respectively, are recommended.

Therapeutic Drug Monitoring of Gentamicin Peak Concentrations in Critically Ill Patients.

BACKGROUND: Adequate gentamicin peak concentrations (Cmax) are important for optimal clinical efficacy. Within a critically ill patient, substantial variability in Cmax can occur over time, hampering the usefulness of therapeutic drug monitoring (TDM). The aim of this study was to evaluate the effect of gentamicin dosing based on Cmax after the first dose on gentamicin target attainment in critically ill patients. METHODS: From gentamicin-treated critically ill patients, dosing information, clinical parameters, and serum concentrations were collected prospectively. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling to estimate Cmax after each dose. To evaluate the usefulness of routine TDM, percentages of Cmax within (%Cther, 15-20 mg/L), above (>20 mg/L), and below (%Csubther, <15 mg/L) the therapeutic range after the first and second doses were compared. In addition, simulations were performed to evaluate the impact of TDM. RESULTS: Four hundred sixteen measurements from 59 patients receiving 130 gentamicin doses were included. In the 30 patients who received >1 dose, TDM increased %Cther from 40% after a first median dose of 5.0 mg/kg to 50% after the second dose, and decreased %Csubther from 47% to 30%. Simulations using a 5 mg/kg starting dose revealed %Cther after the second dose of 28.4% without and 36.8% with TDM and %Csubther of 56.9% and 29.3%, respectively. Increasing the simulated starting dose to 6 mg/kg increased %Cther after the first dose from 27.7% to 33.5% and decreased %Csubther from 58.6% to 35.6%. TDM after a first dose of 6 mg/kg had no substantial effect on %Cther or %Csubther after the second dose. CONCLUSIONS: Gentamicin dosing based on Cmax after the first dose increased %Cther and decreased %Csubther, but did not result in therapeutic Cmax in half of the patients. When simulating a higher starting dose, %Csubther after the first dose decreased, and TDM showed no additional influence. These data suggest that a starting dose of 6 mg/kg should be considered and that repeated Cmax measurements are not of added value.

The impact of trimethoprim-sulfamethoxazole as Pneumocystis jiroveci pneumonia prophylaxis on the occurrence of asymptomatic bacteriuria and urinary tract infections among renal allograft recipients: a retrospective before-after study.

BACKGROUND: The international guidelines recommend the administration of trimethoprim-sulfamethoxazole (TMP-SMX) as Pneumocystis jiroveci pneumonia (PJP) prophylaxis for six months after transplantation. The aim of this study is to evaluate the influence of TMP-SMX prophylaxis on the occurrence of asymptomatic bacteriuria (ASB) and urinary tract infections (UTIs) as cystitis and allograft pyelonephritis (AGPN) and its impact on the antimicrobial resistance pattern of causative microorganisms. METHODS: We have conducted a retrospective before-after study in adult renal allograft recipients with one year follow-up after transplantation. We compared the ("after") group that received TMP-SMX as PJP prophylaxis to the ("before") group that did not receive it. RESULTS: In total, 343 renal allograft recipients were analysed, of whom 212 (61.8 %) received TMP-SMX as PJP prophylaxis. In this study, 63 (18.4 %) did only develop ASB without UTI, 26 (7.6 %) developed cystitis and 43 (12.5 %) developed AGPN. The remaining 211 (61.5 %) renal allograft recipients did not develop any bacteriuria at all. Multivariable Cox proportional regression analysis indicated that TMP-SMX as PJP prophylaxis was not associated with reduced prevalence of ASB (Hazard ratio (HR) = 1.52, 95 % CI = 0.79-2.94, p = 0.213), nor with reduced incidence of cystitis (HR = 2.21, 95 % CI = 0.76-6.39, p = 0.144), nor AGPN (HR = 1.12, 95 % CI = 0.57-2.21, p = 0.751). Among the group receiving TMP-SMX as PJP prophylaxis there was a trend was observed in increase of both amoxicillin (86 % versus 70 %) and TMP-SMX (89 % versus 48 %) resistance which already appeared within the first 30 days after TMP-SMX exposure. CONCLUSIONS: Among renal allograft recipients, administration of TMP-SMX as PJP prophylaxis does not prevent ASB nor UTI, however it is associated with tendency towards increased amoxicillin and TMP-SMX resistance.

Diagnosis and management of aspergillosis in the Netherlands: a national survey.

A survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a background of emerging azole resistance in Aspergillus fumigatus routine resistance screening of clinical isolates was performed primarily in the UMCs. Azole resistance rates at the hospital level varied between 5% and 10%, although rates up to 30% were reported in high-risk wards. Voriconazole remained first choice for invasive aspergillosis in 13 out of 16 hospitals. In documented azole resistance 14 out of 16 centres treated patients with liposomal amphotericin B.

Predominant association of Raoultella bacteremia with diseases of the biliary tract.

A case series of 14 patients with Raoultella bacteremia was compared with 28 Klebsiella oxytoca and 28 Klebsiella pneumoniae bacteremia cases. Forty-three percent of Raoultella bacteremia cases were associated with biliary tract disease, compared to 32% and 22% of patients with K. oxytoca and K. pneumoniae bacteremia, respectively.

Inadequate vancomycin therapy in term and preterm neonates: a retrospective analysis of trough serum concentrations in relation to minimal inhibitory concentrations.

BACKGROUND: Vancomycin is effective against gram-positive bacteria and the first-line antibiotic for treatment of proven coagulase-negative staphylococcal infections. The aim of this study is bipartite: first, to assess the percentage of therapeutic initial trough serum concentrations and second, to evaluate the adequacy of the therapeutic range in interrelationship with the observed MIC-values in neonates. METHODS: In this study, preterm and term neonates admitted at a tertiary NICU in the Netherlands from January 2009 to December 2012 and treated with vancomycin for a proven gram-positive infection were included. Trough serum concentrations were measured prior to administration of the 5th dose. Trough concentrations in the range of 10 to 15 mg/L were considered therapeutic. Staphylococcal species minimal inhibitory concentrations (MIC's) were determined using the E-test method. Species identification was performed by matrix-assisted laser desorption/ionisation mass spectrometry. RESULTS: Of the 112 neonates, 53 neonates (47%) had sub-therapeutic initial trough serum concentrations of vancomycin, whereas 22% had supra-therapeutic initial trough serum concentrations. In all patients doses were adjusted on basis of the initial trough concentration. In 40% (23/57) of the neonates the second trough concentration remained sub-therapeutic. MIC's were determined for 30 coagulase-negative Staphylococcus isolates obtained from 19 patients. Only 4 out of 19 subjects had a trough concentration greater than tenfold the MIC. CONCLUSIONS: Forty-seven percent of the neonates had sub-therapeutic initial trough serum concentrations of vancomycin. The MIC-data indicate that the percentages of underdosed patients may be greater. It may be advisable to increase the lower limit of the therapeutic range for European neonates.

Fusariosis in patients with hematological malignancies: Two case reports.

Immunosuppressed patients with hematological malignancies are at risk for invasive fungal infections (IFI), including infections with Fusarium species (spp.), which are increasingly reported. Particularly at risk are patients with acute myeloid leukemia (AML) treated with high-dose cytarabine as remission-induction therapy. Whether cytarabine increases the risk of IFI in comparison to other chemotherapy remains not fully determined. Additionally, no clear correlation between the in vitro established minimal inhibitory concentrations (MICs) of antifungal agents and clinical outcome has been established for fusariosis. To increase awareness and knowledge of invasive fusariosis, we report two cases of Fusarium spp. infections in neutropenic patients following treatment with cytarabine for AML. Despite high MICs for azoles both patients were treated with an azole in combination with liposomal amphotericin B. The combination therapy was successful in one patient, however the other patient did not survive the disseminated Fusarium infection.

Benzylpenicillin concentrations in umbilical cord blood and plasma of premature neonates following intrapartum doses for group B streptococcal prophylaxis.

BACKGROUND AND METHOD: Dutch obstetrics guideline suggest an initial maternal benzylpenicillin dose of 2,000,000 IU followed by 1,000,000 IU every 4 h for group-B-streptococci (GBS) prophylaxis. The objective of this study was to evaluate whether concentrations of benzylpenicillin reached concentrations above the minimal inhibitory concentrations (MIC) in umbilical cord blood (UCB) and neonatal plasma following the Dutch guideline. RESULTS: Forty-six neonates were included. A total of 46 UCB samples and 18 neonatal plasma samples were available for analysis. Nineteen neonates had mothers that received intrapartum benzylpenicillin. Benzylpenicillin in UCB corresponded to concentrations in plasma drawn directly postpartum (R2 = 0.88, p < 0.01). A log-linear regression suggested that benzylpenicillin concentrations in neonates remained above the MIC threshold 0.125 mg/L up to 13.0 h after the last intrapartum dose. CONCLUSIONS: Dutch intrapartum benzylpenicillin doses result in neonatal concentrations above the MIC of GBS.

Dengue in travellers: applicability of the 1975-1997 and the 2009 WHO classification system of dengue fever.

OBJECTIVES: The aim of this study was to assess the applicability and benefits of the new WHO dengue fever guidelines in clinical practice, for returning travellers. METHODS: We compared differences in specificity and sensitivity between the old and the new guidelines for diagnosing dengue and assessed the usefulness in predicting the clinical course of the disease. Also, we investigated whether hypertension, diabetes or allergies, ethnicity or high age influenced the course of disease. RESULTS: In our setting, the old classification, compared with the new, had a marginally higher sensitivity for diagnosing dengue. The new classification had a slightly higher specificity and was less rigid. Patients with dengue who had warning signs as postulated in the new classification were admitted more often than those who had no warning signs (RR, 8.09 [1.80-35.48]). We did not find ethnicity, age, hypertension, diabetes mellitus or allergies to be predictive of the clinical course. CONCLUSIONS: In our cohort of returned travellers, the new classification system did not differ in sensitivity and specificity from the old system to a clinically relevant degree. The guidelines did not improve identification of severe disease.

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review.

Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of short-term empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5-1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration-time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy.

Population Pharmacokinetics and Probability of Target Attainment of Different Dosing Regimens of Ceftazidime in Critically Ill Patients with a Proven or Suspected Pseudomonas aeruginosa Infection.

Altered pharmacokinetics (PK) of hydrophilic antibiotics in critically ill patients is common, with possible consequences for efficacy and resistance. We aimed to describe ceftazidime population PK in critically ill patients with a proven or suspected Pseudomonas aeruginosa infection and to establish optimal dosing. Blood samples were collected for ceftazidime concentration measurement. A population PK model was constructed, and probability of target attainment (PTA) was assessed for targets 100% T > MIC and 100% T > 4 × MIC in the first 24 h. Ninety-six patients yielded 368 ceftazidime concentrations. In a one-compartment model, variability in ceftazidime clearance (CL) showed association with CVVH. For patients not receiving CVVH, variability in ceftazidime CL was 103.4% and showed positive associations with creatinine clearance and with the comorbidities hematologic malignancy, trauma or head injury, explaining 65.2% of variability. For patients treated for at least 24 h and assuming a worst-case MIC of 8 mg/L, PTA was 77% for 100% T > MIC and 14% for 100% T > 4 × MIC. Patients receiving loading doses before continuous infusion demonstrated higher PTA than patients who did not (100% T > MIC: 95% (n = 65) vs. 13% (n = 15); p < 0.001 and 100% T > 4 × MIC: 20% vs. 0%; p = 0.058). The considerable IIV in ceftazidime PK in ICU patients could largely be explained by renal function, CVVH use and several comorbidities. Critically ill patients are at risk for underexposure to ceftazidime when empirically aiming for the breakpoint MIC for P. aeruginosa. A loading dose is recommended.

Fecal microbiota transplantation against intestinal colonization by extended spectrum beta-lactamase producing Enterobacteriaceae: a proof of principle study.

OBJECTIVE: Infections with multidrug-resistant microorganisms are associated with increased hospitalization, medication costs and mortality. Based on our fecal microbiota transplantation (FMT) experience for Clostridium difficile infection, we treated 15 patients carrying ESBL-producing Enterobacteriaceae (ESBL-EB) with FMT. Seven patients underwent a second FMT after 4 weeks when ESBL-EB remained, amounting to a total number of 22 transplants. The objective was decolonization of ESBL-EB. RESULTS: Three out of fifteen (20%) patients were ESBL-negative at 1, 2 and 4 weeks after the first transplant, while six out of 15 (40%) were negative after the second transplant. Comparison of fecal microbiota at baseline and 4 weeks after FMT revealed restoration of microbial diversity after FMT and a microbial shift towards donor composition. Finally, we suggest several possible factors of response to therapy, such as donor-recipient microbiota match and number of FMTs. Therefore, FMT can be an effective treatment in patients carrying ESBL-EB. Response may be determined by microbiota composition and number of FMT procedures. Trial registration ISRCTN ISRCTN48328635 Registered 11 October 2017, retrospectively registered.

Predictive performance of a gentamicin population pharmacokinetic model in two western populations of critically ill patients.

External validation of population pharmacokinetic (PK) models is warranted before they can be clinically applied to aid in antibiotic dose selection. The primary objective of this study was to assess the predictive performance of a gentamicin population PK model in intensive care unit (ICU) patients in two independent western populations of critically ill patients. METHODS: Data were collected from the ICU where the model was developed (Academic Medical Centre, Amsterdam [AMC]) and from the Centre Hospitalier Universitaire de Nîmes (CHU Nîmes). Primary endpoints were bias and accuracy. The model was regarded as valid if bias was not significantly different from 0 and accuracy was equal to or less than 2.5 mg/L. Non-linear mixed-effects modelling (NONMEM) was used for data analysis. RESULTS: The AMC validation dataset consisted of 192 samples from 66 ICU patients and the CHU Nîmes dataset of 230 gentamicin samples from 50 ICU patients. The structural model predicted the gentamicin plasma concentrations in the AMC population with a non-significant bias (0.35, 95%CI: -0.11-0.81) and a sufficient accuracy of 2.5 mg/L (95%CI: 2.3-2.8). The gentamicin plasma concentrations were overpredicted in the CHU Nîmes population with a significant bias of 4.8 mg/L (95%CI: 4.00-5.62) and an accuracy of 5.5 mg/L (95%CI: 4.7-6.2). CONCLUSION: The model is valid for use in the AMC ICU population but not in the CHU Nîmes ICU population. This illustrates that caution is needed when using a population PK model in an external population.