Systematic Evaluation of Pharmacokinetic Models for Model-Informed Precision Dosing of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

The altered pharmacokinetics of renally cleared drugs such as meropenem in critically ill patients receiving continuous renal replacement therapy (CRRT) might impact target attainment. Model-informed precision dosing (MIPD) is applied to individualize meropenem dosing. However, most population pharmacokinetic (PopPK) models developed to date have not yet been evaluated for MIPD. Eight PopPK models based on adult CRRT patients were identified in a systematic literature research and encoded in NONMEM 7.4. A data set of 73 CRRT patients from two different study centers was used to evaluate the predictive performance of the models using simulation and prediction-based diagnostics for i) a priori dosing based on patient characteristics only and ii) Bayesian dosing by including the first measured trough concentration. Median prediction error (MPE) for accuracy within |20%| (95% confidence intervals including zero) and median absolute prediction error (MAPE) for precision ≤ 30% were considered clinically acceptable. For a priori dosing, most models (n = 5) showed accuracy and precision MPE within |20%| and MAPE <35%. The integration of the first measured meropenem concentration improved the predictive performance of all models (median MAPE decreased from 35.4 to 25.0%; median MPE decreased from 21.8 to 4.6%). The best predictive performance for intermittent infusion was observed for the O'Jeanson model, including residual diuresis as covariate (a priori and Bayesian dosing MPE within |2%|, MAPE <30%). Our study revealed the O'Jeanson model as the best-predicting model for intermittent infusion. However, most of the selected PopPK models are suitable for MIPD in CRRT patients when one therapeutic drug monitoring sample is available.

Antibiotic Stewardship and Therapeutic Drug Monitoring of ß-Lactam Antibiotics: Is There a Link? An Opinion Paper.

PURPOSE: In critically ill patients, changes in the pharmacokinetics (PK) of ß-lactams can lead to significant variations in serum concentrations, with possibly detrimental effects on outcomes. The utilization of individually calculated doses, extended infusion regimen, and therapeutic drug monitoring (TDM)-guided dose adjustments can mitigate the PK changes and help to achieve and attain an individual PK target. METHODS: We reviewed relevant literature from 2004 to 2021 using 4 search engines (PubMed, Web of Science, Scopus, and Google Scholar). Unpublished clinical data were also examined. RESULTS: TDM-guided, individualized dosing strategies facilitated PK target attainment and improved patient outcomes. TDM-guided therapy is a core concept of individualized dosing that increases PK target attainment and identifies possible toxic ß-lactam concentrations. CONCLUSIONS: Individualized dosing and TDM facilitate the rational use of ß-lactams and are integral for antibiotic stewardship interventions in critical care, affording the optimal exposure of both pathogen and drugs, along with enhanced treatment efficacy and reduced emergence of antimicrobial resistance.

What Are the Predictors for Achieving Therapeutic Levetiracetam Serum Concentrations in Adult Neurological Patients?

BACKGROUND: Emerging studies suggest that levetiracetam pharmacokinetics can be difficult to predict in certain special patient populations, including the elderly, critically ill patients, and pregnant women. OBJECTIVE: To determine clinical characteristics that predict the attainment of target serum concentrations in a heterogeneous group of patients prescribed levetiracetam. METHODS: A retrospective observational study was conducted in adult neurological patients prescribed levetiracetam for the treatment or prophylaxis of seizures. Serum samples were collected after steady-state was reached, with a trough/steady-state serum concentration between 6 and 20 mg/L considered therapeutic. Logistic regression was used to identify significant predictors associated with the attainment of therapeutic concentrations. RESULTS: One-hundred thirty patients (63 male) were included. The median (interquartile ranges) serum trough/steady-state concentration (Cmin/ss) was 16.2 (9.8-26.1) mg/L. The dose-normalized median (interquartile range) Cmin/ss was 11.5 (7.0-16.5) mg/L. The coefficient of variation of Cmin/ss and dose-normalized Cmin/ss were 69.4% and 64.2%, respectively. A weak correlation was observed between levetiracetam Cmin/ss and patient age (r = 0.21; P = 0.020), creatinine clearance (r = -0.26; P = 0.004), and daily dose (r = 0.42; P < 0.001). Logistic regression analysis identified age and daily levetiracetam dose as significant factors predicting target Cmin/ss attainment. The influence of concomitant antiepileptic therapy was not determined. CONCLUSIONS: Age and daily dose were the most significant predictors of levetiracetam target-concentration attainment and should be considered in further investigations to develop a dosing algorithm for optimal levetiracetam therapy.

CSF penetration of vancomycin in critical care patients with proven or suspected ventriculitis: a prospective observational study.

BACKGROUND: Vancomycin is recommended for ventriculitis. However, penetration into the CNS is relatively poor. OBJECTIVES: To investigate the population pharmacokinetics of vancomycin in serum and CSF in critical care patients with proven or suspected CNS infections from neurosurgical procedures. PATIENTS AND METHODS: This was an observational pharmacokinetic study in critical care patients with proven or suspected CNS infections receiving intravenous vancomycin. Multiple blood and intraventricular CSF samples were collected. Population pharmacokinetic analysis and simulation were undertaken with ADAPT5 and Pmetrics. RESULTS: A total of 187 blood and CSF samples were collected from 21 patients. The median (range) Cmax and Cmin concentrations in serum were 25.67 (10.60-50.78) and 9.60 (4.46-23.56) mg/L, respectively, with a median daily dose of 2500 (500-4000) mg. The corresponding median concentrations in CSF were 0.65 (<0.24-3.83) mg/L and 0.58 (<0.24-3.95) mg/L, respectively. The median AUC0-24 in serum and CSF was 455.09 and 14.10 mg·h/L, respectively. A three-compartment linear population pharmacokinetic model best fitted the observed data. Vancomycin demonstrated poor penetration into CSF, with a median CSF/serum ratio of 3% and high intersubject pharmacokinetic variability of its penetration. CONCLUSIONS: Therapeutic drug monitoring in both serum and CSF and higher daily doses may be an option to ensure adequate trough levels and to optimize patient therapy. Novel dosing strategies designed to reduce renal toxicity, such as administration by continuous infusion, should be investigated in further clinical studies to avoid antibiotic underexposure in CSF.

Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience.

PURPOSE: Standard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with ß-lactams in critically ill patients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically ill patients. METHODS: This is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2-4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)]. RESULTS: PK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CLPIP): no RRT CLPIP 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CLPIP 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CLPIP 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m2 significantly increased CLPIP 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33-64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]). CONCLUSION: TDM-guided CI of PIP is safe in critically ill patients and improves PK-target attainment. Exposure to defined PK-targets impacts patient mortality while lower and higher than intended SCs may influence the outcome of critically ill patients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.

Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model.

Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEM® 7.3 based on steady-state meropenem concentrations (CSS) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRCG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (CSS ≥8 mg/L) and potentially increased likelihood of adverse drug reactions (CSS >32 mg/L). Results: In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P0.05 - P0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/3940 mg were required to reach a target CSS = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5%) was associated with these doses. Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.

Population pharmacokinetics and dosing simulations of ceftazidime in critically ill patients receiving sustained low-efficiency dialysis.

Objectives: To describe the population PKs of ceftazidime in critically ill patients receiving sustained low-efficiency dialysis (SLED). Patients and methods: This study was performed in ICUs of a university hospital. We collected blood samples during three consecutive days of SLED sessions in patients receiving ceftazidime. Concentration versus time curves were analysed using a population PKs approach with Pmetrics ® . Monte Carlo simulation for the first 24 h including a 6 h SLED session was performed with the final model. The fractional target attainment against the MIC of Pseudomonas aeruginosa was executed using targets of 50 and 100% fT > MIC . Results: In total, 211 blood samples of 16 critically ill patients under SLED were collected. SLED treatments were 299.3 (68.4) min in duration. A two-compartment linear population PK model was most appropriate. The mean (SD) CL of ceftazidime on SLED, and off SLED were 5.32 (3.2), 1.06 (1.0) L/h respectively. The PTA for 50% fT > MIC for a dose of 1 g intravenously every 8 h was 98%. Assuming a target of 100% fT > MIC a dose of 2 g every 12 h covers isolates with MIC ≤8 mg/L with a PTA of 96%. Conclusion: In critically ill patients receiving SLED, ceftazidime 1 g every 8 h and ceftazidime 2 g every 12 h appear to be sufficient for achieving traditional (50% fT > MIC ) and aggressive PD targets (100% fT > MIC ) for susceptible isolates (MIC ≤8 mg/L), respectively.

Population pharmacokinetics of meropenem in elderly patients: dosing simulations based on renal function.

OBJECTIVES: The aim of this study was to evaluate different dosage regimens of meropenem in elderly patients in relation with renal function using a population pharmacokinetic (popPK) model. METHODS: The data of 178 elderly patients treated with meropenem was collected from different sources. A popPK model was developed by using NONMEM® and the influence of different covariates on meropenem CL and V1 was observed. Monte Carlo dosing simulations were performed at steady state to observe the % T > MIC for targets of 40, 60 and 80% of dosage intervals at different levels of creatinine clearance (CLCR). RESULTS: The data was described by a two-compartment model and the values of parameter estimates for CL, V1, Q and V2 were 5.27 L/h, 17.2 L, 9.92 L/h and 10.6 L, respectively. The CLCR, body weight and centre had a significant influence on meropenem CL while no direct influence of age was observed. Extended infusions had pharmacokinetic and pharmacodynamic (PK/PD) breakpoint one dilution greater than corresponding short infusion regimens for each target of % T > MIC. CONCLUSION: Meropenem CL was significantly lower in the elderly compared to CL reported in younger patients due to the reduced renal function. An extended infusion of 1000 mg q8h can be considered for empirical treatment of infections in elderly patients when CLCR is ≤ 50 mL/min. A continuous infusion of 3000 mg daily dose is preferred if CLCR > 50 mL/min. However, a higher daily dose of meropenem would be required for resistant strains (MIC >8 mg/L) of bacteria if CLCR is >100 mL/min.

What is the effect of obesity on piperacillin and meropenem trough concentrations in critically ill patients?

OBJECTIVES: The objectives of this study were to determine the effects of obesity on unbound trough concentrations and on the achievement of pharmacokinetic (PK)/pharmacodynamic (PD) targets of piperacillin and meropenem in critically ill patients. METHODS: This study retrospectively analysed therapeutic-drug-monitoring data from ICU databases in Australia, Germany and Spain, as well as from a large PK study. The presence of obesity was defined as a BMI ≥30 kg/m(2), and patients were also categorized based on level of renal function. The presence of obesity was compared with unbound piperacillin and meropenem trough concentrations. We also used logistic regression to describe factors associated with the achievement of the PK/PD targets, an unbound concentration maintained above the MIC breakpoint (100% fT>MIC and 100% fT>4×MIC) of Pseudomonas aeruginosa. RESULTS: In all, 1400 patients were eligible for inclusion in the study. The median age and weight were 67 years (IQR 52-76 years) and 79 kg (69-90 kg), respectively, and 65% of participants were male. Significantly lower median piperacillin trough concentrations [29.4 mg/L (IQR 17.0-58.0 mg/L)] were found in obese patients compared with non-obese patients [42.0 mg/L (21.5-73.5 mg/L)] (P = 0.001). There was no difference for meropenem trough concentrations [obese 10.3 mg/L (IQR 4.8-16.0 mg/L) versus non-obese 11.0 mg/L (4.3-18.5 mg/L); P = 0.296]. Using logistic regression, we found that the presence of obesity was not associated with achievement of 100% fT>MIC, but the use of prolonged infusion, a creatinine clearance ≤100 mL/min, increasing age and female gender were for various PK/PD targets for both piperacillin and meropenem (P < 0.05). CONCLUSIONS: This large dataset has shown that the presence of obesity in critically ill patients may affect piperacillin, but not meropenem, unbound trough concentrations.

Cerebrospinal fluid penetration of meropenem in neurocritical care patients with proven or suspected ventriculitis: a prospective observational study.

BACKGROUND: Ventriculitis is a complication of temporary intraventricular drains. The limited penetration of meropenem into the cerebrospinal fluid (CSF) is well known. However, ventricular CSF pharmacokinetic data in patients with ventriculitis are lacking. The aim of this study was to evaluate meropenem pharmacokinetics in the serum and CSF of neurocritical care patients with proven or suspected ventriculitis. METHODS: We conducted an observational pharmacokinetic study of neurocritical care patients with proven or suspected ventriculitis receiving meropenem. Multiple blood and CSF samples were taken and were described using nonparametric pharmacokinetic modelling with Pmetrics. RESULTS: In total, 21 patients (median age 52 years, median weight 76 kg) were included. The median (range) of peak and trough concentrations in serum were 20.16 (4.40-69.00) mg/L and 2.54 (0.00-31.40) mg/L, respectively. The corresponding peak and trough concentrations in CSF were 1.20 (0.00-6.20) mg/L and 1.28 (0.00-4.10) mg/L, respectively, with a median CSF/serum ratio (range) of 0.09 (0.03-0.16). Median creatinine clearance ranged from 60.7 to 217.6 ml/minute (median 122.5 ml/minute). A three-compartment linear population pharmacokinetic model was most appropriate. No covariate relationships could be supported for any of the model parameters. Meropenem demonstrated poor penetration into CSF, with a median CSF/serum ratio of 9 % and high interindividual pharmacokinetic variability. CONCLUSIONS: Administration of higher-than-standard doses of meropenem and therapeutic drug monitoring in both serum and CSF should be considered to individualise meropenem dosing in neurocritical care patients with ventriculitis.

Decreased Linezolid Serum Concentrations in Three Critically Ill Patients: Clinical Case Studies of a Potential Drug Interaction between Linezolid and Rifampicin.

Linezolid is a valuable treatment option for treating infections caused by multi-resistant gram-positive pathogens. Lack of effective linezolid levels due to the co-administration of rifampicin has been described in healthy subjects. However, the clinical significance of this potential drug interaction (DI) for critically ill patients is still unclear. This was a retrospective analysis of 3 critically ill patients with the combination therapy of linezolid and rifampicin or rifampicin pre-treatment. Despite increasing the dose of linezolid, the majority of observed linezolid trough concentrations in all 3 patients were below 2 mg/l. Furthermore, linezolid trough concentrations remained below 2 mg/l after discontinuation of rifampicin. This potential DI between linezolid and rifampicin could lead to treatment failure. Therefore, we strongly recommend that linezolid serum concentrations be monitored in patients with rifampicin co-administration or rifampicin pretreatment.

An international, multicentre survey of ß-lactam antibiotic therapeutic drug monitoring practice in intensive care units.

OBJECTIVES: Emerging evidence supports the use of therapeutic drug monitoring (TDM) of ß-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for ß-lactam TDM in ICUs. METHODS: A questionnaire survey was developed to describe various aspects relating to the conduct of ß-lactam TDM in an ICU setting. Data sought included: ß-lactams chosen for TDM, inclusion criteria for selecting patients, blood sampling strategy, analytical methods, pharmacokinetic (PK)/pharmacodynamic (PD) targets and dose adjustment strategies. RESULTS: Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the ß-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of ß-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT>MIC up to 100% fT>4×MIC) and dose adjustment strategies used by each of the sites. CONCLUSIONS: Large variations were found in the type of ß-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing ß-lactam dosing with TDM.

No Sequestration of Commonly Used Anti-Infectives in the Extracorporeal Membrane Oxygenation (ECMO) Circuit-An Ex Vivo Study.

Patients undergoing extracorporeal membrane oxygenation (ECMO) often require therapy with anti-infective drugs. The pharmacokinetics of these drugs may be altered during ECMO treatment due to pathophysiological changes in the drug metabolism of the critically ill and/or the ECMO therapy itself. This study investigates the latter aspect for commonly used anti-infective drugs in an ex vivo setting. A fully functional ECMO device circulated an albumin-electrolyte solution through the ECMO tubes and oxygenator. The antibiotic agents cefazolin, cefuroxim, cefepime, cefiderocol, linezolid and daptomycin and the antifungal agent anidulafungin were added. Blood samples were taken over a period of four hours and drug concentrations were measured via high-pressure liquid chromatography (HPLC) with UV detection. Subsequently, the study analyzed the time course of anti-infective concentrations. The results showed no significant changes in the concentration of any tested anti-infectives throughout the study period. This ex vivo study demonstrates that the ECMO device itself has no impact on the concentration of commonly used anti-infectives. These findings suggest that ECMO therapy does not contribute to alterations in the concentrations of anti-infective medications in severely ill patients.

Software- and TDM-Guided Dosing of Meropenem Promises High Rates of Target Attainment in Critically Ill Patients.

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The optimal dosing strategy for beta-lactams in critically ill patients, particularly in septic patients, is an ongoing matter of discussion. This retrospective study aimed to evaluate the success of software-guided empiric meropenem dosing (CADDy, Calculator to Approximate Drug-Dosing in Dialysis) with subsequent routine meropenem measurements and expert clinical pharmacological interpretations. Adequate therapeutic drug exposure was defined as concentrations of 8-16 mg/L, whereas concentrations of 16-24 mg/L were defined as moderately high and concentrations >24 mg/L as potentially harmful. A total of 91 patients received meropenem as a continuous infusion (229 serum concentrations), of whom 60% achieved 8-16 mg/L, 23% achieved 16-24 mg/L, and 10% achieved unnecessarily high and potentially harmful meropenem concentrations >24 mg/L in the first 48 h using the dosing software. No patient showed concentrations <2 mg/L using the dosing software in the first 48 h. With a subsequent TDM-guided dose adjustment, therapeutic drug exposure was significantly (p ≤ 0.05) enhanced to 70%. No patient had meropenem concentrations >24 mg/L with TDM-guided dose adjustments. The combined use of dosing software and consecutive TDM promised a high rate of adequate therapeutic drug exposures of meropenem in patients with sepsis and septic shock.

Daptomycin Pharmacokinetics in Blood and Wound Fluid in Critical Ill Patients with Left Ventricle Assist Devices.

Daptomycin is a cyclic lipopeptide antibiotic with bactericidal effects against multidrug-resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). For critically ill patients, especially in the presence of implants, daptomycin is an important therapeutic option. Left ventricle assist devices (LVADs) can be utilized for intensive care patients with end-stage heart failure as a bridge to transplant. We conducted a single-center prospective trial with critically ill adults with LVAD who received prophylactic anti-infective therapy with daptomycin. Our study aimed to evaluate the pharmacokinetics of daptomycin in the blood serum and wound fluids after LVAD implantation. Daptomycin concentration were assessed over three days using high-performance liquid chromatography (HPLC). We detected a high correlation between blood serum and wound fluid daptomycin concentration at 12 h (IC95%: 0.64 to 0.95; r = 0.86; p < 0.001) and 24 h (IC95%: -0.38 to 0.92; r = 0.76; p < 0.001) after antibiotic administration. Our pilot clinical study provides new insights into the pharmacokinetics of daptomycin from the blood into wound fluids of critically ill patients with LVADs.

Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting.

PURPOSE: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models. METHODS: A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision. RESULTS: The evaluation revealed a large inter-model variability (A: MPE - 135.6-78.3% and MAPE 35.7-135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE|median_all_models 45.1/67.5%; MAPEmedian_all_models 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE - 9.8/- 5.9/- 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models. CONCLUSION: The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM.

Ciprofloxacin in Patients Undergoing Extracorporeal Membrane Oxygenation (ECMO): A Population Pharmacokinetic Study.

Extracorporeal membrane oxygenation (ECMO) is utilized to temporarily sustain respiratory and/or cardiac function in critically ill patients. Ciprofloxacin is used to treat nosocomial infections, but data describing the effect of ECMO on its pharmacokinetics is lacking. Therefore, a prospective, observational trial including critically ill adults (n = 17), treated with ciprofloxacin (400 mg 8-12 hourly) during ECMO, was performed. Serial blood samples were collected to determine ciprofloxacin concentrations to assess their pharmacokinetics. The pharmacometric modeling was performed (NONMEM®) and utilized for simulations to evaluate the probability of target attainment (PTA) to achieve an AUC0-24/MIC of 125 mg·h/L for ciprofloxacin. A two-compartment model most adequately described the concentration-time data of ciprofloxacin. Significant covariates on ciprofloxacin clearance (CL) were plasma bicarbonate and the estimated glomerular filtration rate (eGFR). For pathogens with an MIC of ≤0.25 mg/L, a PTA of ≥90% was attained. However, for pathogens with an MIC of ≥0.5 mg/L, plasma bicarbonate ≥ 22 mmol/L or eGFR ≥ 10 mL/min PTA decreased below 90%, steadily declining to 7.3% (plasma bicarbonate 39 mmol/L) and 21.4% (eGFR 150 mL/min), respectively. To reach PTAs of ≥90% for pathogens with MICs ≥ 0.5 mg/L, optimized dosing regimens may be required.

Validation and Application of an HPLC-UV Method for Routine Therapeutic Drug Monitoring of Dalbavancin.

Dalbavancin is emerging as a promising alternative in the ambulant treatment of gram-positive infections that require long-term antibiotic treatment such as osteomyelitis, prosthetic joint infections, and endocarditis. The aim of the current study was to develop and validate a simple, rapid, and cost-effective high-performance liquid chromatography-ultraviolet spectrometry (HPLC-UV) method for the quantification of dalbavancin. Sample clean-up included a protein precipitation protocol, followed by chromatographic separation on a reverse phase HPLC column (C-18) with gradient elution of the mobile phase. Quantification was performed with the internal standard (caffeine) method. Linear relationships between peak area responses and drug concentrations were obtained in the range of 12.5-400 mg/L. The variation coefficient of precision and the bias of accuracy (both inter- and intraday) were less than 10%. The limit of quantification (LOQ) was 12.5 mg/L. The simple and reliable HPLC-UV assay described is a powerful tool for routine therapeutic drug monitoring (TDM) of dalbavancin in human serum in clinical laboratories. With a total process time of approximately 20 min, it allows for accurate and selective quantification up to the expected pharmacokinetic peak concentrations. The method was successfully used to analyze subsequent serum samples of three patients and showed good performance in monitoring serum levels.

Liver function, quantified by the LiMAx test, as a predictor for the clinical outcome of critically ill patients treated with linezolid.

BACKGROUND: Critically ill patients commonly suffer from infections that require antimicrobial therapy. In previous studies, liver dysfunction was shown to have an essential impact on the dose selection in these patients. This pilot study aims to assess the influence of liver dysfunction, measured by the novel LiMAx test, on clinical outcomes in critically ill patients treated with linezolid. METHODS: Twenty-nine critically ill patients were included and treated with linezolid. Indications for linezolid therapy were secondary or tertiary peritonitis (46.7%), bloodstream infection (6.7%) and 46.7% were other infections with gram-positive bacteria. Linezolid Cmin, maximal liver function capacity (LiMAx test) and plasma samples were collected while linezolid therapy was in a steady-state condition. Furthermore, potential factors for the clinical outcome were investigated using logistic regression analysis. Clinical cure was defined as the resolution or significant improvement of clinical symptoms without using additional antibiotic therapy or intervention. RESULTS: Cured patients presented lower median linezolid Cmin yet a significantly higher mean LiMAx-value compared to the clinical failure group (1.9 mg/L vs. 5.1 mg/L) (349 µg/kg/h vs. 131 µg/kg/h). In the logistic regression model, LiMAx < 178 µg/kg/h was the only independent predictor of clinical failure with a sensitivity of 77% and specificity of 93%. CONCLUSIONS: The LiMAx test predicts clinical failure more precisely than linezolid trough levels in critically ill surgical patients. Therefore liver failure may have a stronger impact on the outcome of critically ill surgical patients than low linezolid Cmin. While linezolid Cmin failed to predict patient's outcome, LiMAx results were the only independent predictor of clinical failure.

Population pharmacokinetics and toxicodynamics of continuously infused linezolid in critically ill patients.

OBJECTIVES: Linezolid is a treatment option against multi-drug-resistant Gram-positive pathogens. Continuous infusion of linezolid has been proposed to optimize antimicrobial exposure, although pharmacokinetic data from large patient cohorts are lacking. METHODS: Population pharmacokinetics and the time-dependent association between linezolid exposure and the occurrence of thrombocytopenia in 120 critically ill patients were described. Monte Carlo simulations evaluated pharmacokinetic/pharmacodynamic/toxicodynamic target attainment in relation to body weight and creatinine clearance for continuously infused doses of 300-2400 mg/day. RESULTS: Linezolid pharmacokinetics were highly variable (interindividual variability of clearance: 52.8% coefficient of variation). Non-linear clearance was quantified, which decreased from 6.82 to 3.82 L/h within 3-6 days in the population. A relationship between linezolid exposure and platelet count over time was established. For standard dosing (1200 mg/day), the model predicted Grade 2, 3 or 4 thrombocytopenia (<75 × 103/µL, <50 × 103/µL and <25 × 103/µL) in 21.7%, 10.4% and 2.5% of patients at day 14, respectively. Patients with impaired renal function displayed higher risk. The overall probability of Grade 3 thrombocytopenia could be reduced from 10.4% using standard dosing to 6.3% if a linezolid steady state plasma concentration of 7 mg/L is targeted, suggesting a value of therapeutic drug monitoring (TDM). CONCLUSION: Dosing linezolid by continuous infusion should include considerations of creatinine clearance and body weight to maximize the achievement of therapeutic exposures. However, due to the high variability in individual dose, optimization using TDM seems necessary to optimize linezolid dosing under continuous infusion to avoid toxicity, particularly if longer treatment courses are expected.