scholarly journals An international survey on aminoglycoside practices in critically ill patients: the AMINO III study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claire Roger ◽  
◽  
Benjamin Louart ◽  
Loubna Elotmani ◽  
Greg Barton ◽  
...  
Keyword(s):  
Septic Shock ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Multivariable Analysis ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Icu Patients ◽  
Optimal Dosing ◽  
Wide Variability ◽  
Dosing Strategy

Abstract Background While aminoglycosides (AG) have been used for decades, debate remains on their optimal dosing strategy. We investigated the international practices of AG usage specifically regarding dosing and therapeutic drug monitoring (TDM) in critically ill patients. We conducted a prospective, multicentre, observational, cohort study in 59 intensive-care units (ICUs) in 5 countries enrolling all ICU patients receiving AG therapy for septic shock. Results We enrolled 931 septic ICU patients [mean ± standard deviation, age 63 ± 15 years, female 364 (39%), median (IQR) SAPS II 51 (38–65)] receiving AG as part of empirical (761, 84%) or directed (147, 16%) therapy. The AG used was amikacin in 614 (66%), gentamicin in 303 (33%), and tobramycin in 14 (1%) patients. The median (IQR) duration of therapy was 2 (1–3) days, the number of doses was 2 (1–2), the median dose was 25 ± 6, 6 ± 2, and 6 ± 2 mg/kg for amikacin, gentamicin, and tobramycin respectively, and the median dosing interval was 26 (23.5–43.5) h. TDM of Cmax and Cmin was performed in 437 (47%) and 501 (57%) patients, respectively, after the first dose with 295 (68%) patients achieving a Cmax/MIC > 8 and 353 (71%) having concentrations above Cmin recommended thresholds. The ICU mortality rate was 27% with multivariable analysis showing no correlation between AG dosing or pharmacokinetic/pharmacodynamic target attainment and clinical outcomes. Conclusion Short courses of high AG doses are mainly used in ICU patients with septic shock, although wide variability in AG usage is reported. We could show no correlation between PK/PD target attainment and clinical outcome. Efforts to optimize the first AG dose remain necessary. Trial registration Clinical Trials, NCT02850029, registered on 29th July 2016, retrospectively registered, https://www.clinicaltrials.gov

scholarly journals 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

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 612
Author(s):  
Annabel Werumeus Buning ◽  
Caspar J. Hodiamont ◽  
Natalia M. Lechner ◽  
Margriet Schokkin ◽  
Paul W. G. Elbers ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Hematologic Malignancy ◽  
Compartment Model ◽  
Target Attainment ◽  
Worst Case ◽  
Optimal Dosing ◽  
Population Pk ◽  
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.

scholarly journals Colistin-Resistant Acinetobacter Baumannii Bacteremia: A Serious Threat for Critically Ill Patients

2020 ◽  
Vol 8 (2) ◽  
pp. 287 ◽  
Author(s):  
Georgios Papathanakos ◽  
Ioannis Andrianopoulos ◽  
Athanasios Papathanasiou ◽  
Efthalia Priavali ◽  
Despoina Koulenti ◽  
...  
Keyword(s):  
Septic Shock ◽  
Acinetobacter Baumannii ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Clinical Problem ◽  
Hospital Infections ◽  
Colistin Resistance ◽  
Icu Patients ◽  
Icu Admission ◽  
Comorbidity Index

The prevalence of acinetobacter baumannii (AB) as a cause of hospital infections has been rising. Unfortunately, emerging colistin resistance limits therapeutic options and affects the outcome. The aim of the study was to confirm our clinically-driven hypothesis that intensive care unit (ICU) patients with AB resistant-to-colistin (ABCoR) bloodstream infection (BSI) develop fulminant septic shock and die. We conducted a 28-month retrospective observational study including all patients developing AB infection on ICU admission or during ICU stay. From 622 screened patients, 31 patients with BSI sepsis were identified. Thirteen (41.9%) patients had ABCoR BSI and 18/31 (58.1%) had colistin-susceptible (ABCoS) BSI. All ABCoR BSI patients died; of them, 69% (9/13) presented with fulminant septic shock and died within the first 3 days from its onset. ABCoR BSI patients compared to ABCoS BSI patients had higher mortality (100% vs. 50%, respectively (p = 0.001)), died sooner (p = 0.006), had lower pH (p = 0.004) and higher lactate on ICU admission (p = 0.0001), and had higher APACHE II (p = 0.01) and Charlson Comorbidity Index scores (p = 0.044). In conclusion, we documented that critically ill patients with ABCoR BSI exhibit fulminant septic shock with excessive mortality. Our results highlight the emerging clinical problem of AB colistin resistance among ICU patients.

scholarly journals Model-Optimized Fluconazole Dose Selection for Critically Ill Patients Improves Early Pharmacodynamic Target Attainment without the Need for Therapeutic Drug Monitoring

2020 ◽  
Vol 65 (3) ◽  
Author(s):  
Indy Sandaradura ◽  
Jessica Wojciechowski ◽  
Deborah J. E. Marriott ◽  
Richard O. Day ◽  
Sophie Stocker ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Dose Selection ◽  
Dose Individualization

ABSTRACT Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study. The objective of this study was to evaluate fluconazole drug exposure in critically ill patients comparing a novel model-optimized dose selection method with established approaches over a standard 14-day (336-h) treatment course. Target attainment was evaluated in a representative population of 1,000 critically ill adult patients for (i) guideline dosing (800-mg loading and 400-mg maintenance dosing adjusted to renal function), (ii) guideline dosing followed by therapeutic drug monitoring (TDM)-guided dose adjustment, and (iii) model-optimized dose selection based on patient factors (without TDM). Assuming a MIC of 2 mg/liter, free fluconazole 24-h area under the curve (fAUC24) targets of ≥200 mg · h/liter and <800 mg · h/liter were used for assessment of target attainment. Guideline dosing resulted in underexposure in 21% of patients at 48 h and in 23% of patients at 336 h. The TDM-guided strategy did not influence 0- to 48-h target attainment due to inherent procedural delays but resulted in 37% of patients being underexposed at 336 h. Model-optimized dosing resulted in ≥98% of patients meeting efficacy targets throughout the treatment course, while resulting in less overexposure compared with guideline dosing (7% versus 14%) at 336 h. Model-optimized dose selection enables fluconazole dose individualization in critical illness from the outset of therapy and should enable reevaluation of the comparative effectiveness of this drug in patients with severe fungal infections.

scholarly journals Suboptimal Dosing of Fluconazole in Critically Ill Patients: Time To Rethink Dosing

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Eline W. Muilwijk ◽  
Dylan W. de Lange ◽  
Jeroen A. Schouten ◽  
Roeland E. Wasmann ◽  
Rob ter Heine ◽  
...  
Keyword(s):  
Renal Function ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Open Label ◽  
Time Curve ◽  
Icu Patients ◽  
Unbound Fraction ◽  
Multicenter Observational Study ◽  
The Impact

ABSTRACT Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.)

scholarly journals Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness—Experience and Recommendations from One Year in Routine Clinical Practice

Antibiotics ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 131
Author(s):  
Christina Scharf ◽  
Michael Paal ◽  
Ines Schroeder ◽  
Michael Vogeser ◽  
Rika Draenert ◽  
...  
Keyword(s):  
Renal Function ◽  
Clinical Practice ◽  
Therapeutic Drug Monitoring ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Beta Lactam ◽  
Target Attainment ◽  
Number Of Patients

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem, r = 0.53; piperacillin, r = 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment.

Can 1 μg of Cosyntropin Be Used to Evaluate Adrenal Insufficiency in Critically Ill Patients?

2005 ◽  
Vol 39 (4) ◽  
pp. 691-698 ◽  
Author(s):  
Elizabeth F Kozyra ◽  
Randy S Wax ◽  
Lisa D Burry
Keyword(s):  
Septic Shock ◽  
Intensive Care ◽  
Adrenal Insufficiency ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Large Scale ◽  
Relative Adrenal Insufficiency ◽  
Acth Stimulation ◽  
Icu Patients ◽  
Insulin Tolerance

OBJECTIVE: To evaluate the utility of cosyntropin 1 μg in assessing adrenal function in critically ill patients. DATA SOURCES: A computerized literature search using MEDLINE, EMBASE, International Pharmaceutical Abstracts, and the Cochrane Database (1966–August 2004) was undertaken for trials evaluating cosyntropin 1 μg using the following search terms: adrenocorticotropin-releasing hormone (ACTH), cosyntropin, adrenal insufficiency, cortisol, corticosteroids, glucocorticoids, sepsis, septic shock, diagnosis, critically ill, intensive care, and critical care. STUDY SELECTION AND DATA SYNTHESIS: Identifying patients with sepsis with relative adrenal insufficiency (AI) using cosyntropin testing may identify those likely to benefit from corticosteroids. The results of 5 heterogeneous studies in non—intensive care unit (ICU) patients suggest that both 1 μg and 250 μg of cosyntropin stimulate similar cortisol responses and that testing using both doses correlates well with results from insulin tolerance testing. Some data from non-ICU patients suggest that the 1-μg test may be more sensitive to detect AI; 3 heterogeneous studies in ICU patients confirmed the improved sensitivity of the 1-μg test. CONCLUSIONS: Use of cosyntropin 1 μg should detect AI in all patients who would have been diagnosed using 250 μg. Unfortunately, all of the clinical trials evaluating the role of corticosteroids in septic shock that used the cosyntropin stimulation test administered 250 μg. Extrapolation of the existing guidelines to treat patients with septic shock testing positive for relative AI using the 1-μg test may provide effective therapy to appropriate patients not diagnosed by the 250-μg testing or may introduce additional adverse effects in patients who should not receive corticosteroids. Large-scale, head-to-head comparison data of steroid effectiveness after 1- and 250-μg ACTH stimulation tests are needed to expand upon these promising results.

scholarly journals Personalized Piperacillin Dosing for the Critically Ill: A Retrospective Analysis of Clinical Experience with Dosing Software and Therapeutic Drug Monitoring to Optimize Antimicrobial Dosing

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 667
Author(s):  
Ute Chiriac ◽  
Daniel C. Richter ◽  
Otto R. Frey ◽  
Anka C. Röhr ◽  
Sophia Helbig ◽  
...  
Keyword(s):  
Septic Shock ◽  
Therapeutic Drug Monitoring ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Therapeutic Drug ◽  
Serum Concentrations ◽  
Severe Infections ◽  
Sepsis And Septic Shock

Optimization of antibiotic dosing is a treatment intervention that is likely to improve outcomes in severe infections. The aim of this retrospective study was to describe the therapeutic exposure of steady state piperacillin concentrations (cPIP) and clinical outcome in critically ill patients with sepsis or septic shock who received continuous infusion of piperacillin with dosing personalized through software-guided empiric dosing and therapeutic drug monitoring (TDM). Therapeutic drug exposure was defined as cPIP of 32–64 mg/L (2–4× the ‘MIC breakpoint’ of Pseudomonas aeruginosa). Of the 1544 patients screened, we included 179 patients (335 serum concentrations), of whom 89% achieved the minimum therapeutic exposure of >32 mg/L and 12% achieved potentially harmful cPIP > 96 mg/L within the first 48 h. Therapeutic exposure was achieved in 40% of the patients. Subsequent TDM-guided dose adjustments significantly enhanced therapeutic exposure to 65%, and significantly reduced cPIP > 96 mg/L to 5%. Mortality in patients with cPIP > 96 mg/L (13/21; 62%) (OR 5.257, 95% CI 1.867–14.802, p = 0.001) or 64–96 mg/L (30/76; 45%) (OR 2.696, 95% CI 1.301–5.586, p = 0.007) was significantly higher compared to patients with therapeutic exposure (17/72; 24%). Given the observed variability in critically ill patients, combining the application of dosing software and consecutive TDM increases therapeutic drug exposure of piperacillin in patients with sepsis and septic shock.

scholarly journals Elimination of fosfomycin during dialysis with the Genius system in septic patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
T. Dimski ◽  
T. Brandenburger ◽  
M. Janczyk ◽  
T. Slowinski ◽  
C. MacKenzie ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Prospective Observational Study ◽  
Kidney Injury ◽  
Serum Levels ◽  
Therapeutic Drug ◽  
Loading Dose ◽  
Dialysis Therapy ◽  
Daily Dialysis ◽  
Wide Variability

AbstractTo assess fosfomycin (FOS) elimination in patients with sepsis and acute kidney injury (AKI) undergoing slow-extended daily dialysis (SLEDD) with the Genius system in a prospective observational study. After ethics committee approval ten patients with sepsis and AKI stage 3 underwent daily SLEDD sessions of eight hours. FOS was applied i.v. at doses of 3 × 5 g per day. FOS serum levels were measured pre- and post hemofilter before, during, and after SLEDD sessions, and instantaneous clearance was calculated. In five of the patients, we analyzed FOS levels after the first dose, in the other five patients serum levels were measured during ongoing therapy. FOS was eliminated rapidly via the hemofilter. FOS clearance decreased from 152 ± 10 mL/min (start of SLEED session) to 43 ± 38 mL/min (end of SLEDD session). In 3/5 first-dose patients after 4–6 h of SLEDD the FOS serum level fell below the EUCAST breakpoint of 32 mg/L for Enterobacterales and Staphylococcus species. In all patients with ongoing fosfomycin therapy serum levels were high and above the breakpoint at all times. FOS toxicity or adverse effects were not observed. FOS serum concentrations exhibit wide variability in critically ill patients with sepsis and AKI. FOS is eliminated rapidly during SLEDD. A loading dose of 5 g is not sufficient to achieve serum levels above the EUCAST breakpoint for common bacteria in all patients, considering that T > MIC > 70% of the dosing interval indicates sufficient plasma levels. We thus recommend a loading dose of 8 g followed by a maintenance dose of 5 g after a SLEDD session in anuric patients. We strongly recommend therapeutic drug monitoring of FOS levels in critically ill patients with AKI and dialysis therapy.

Liquid Chromatography-Tandem Mass Spectrometry to Monitor Unbound and Total Ceftriaxone in Serum of Critically Ill Patients

2020 ◽  
Vol 15 ◽  
Author(s):  
Sjoerd Meenks ◽  
Jos le Noble ◽  
Norbert Foudraine ◽  
Frank de Vries ◽  
Paddy Janssen
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Tandem Mass Spectrometry ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Tandem Mass ◽  
Target Attainment ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

Background: Ceftriaxone is recommended for empiric antimicrobial therapy in patients with sepsis. Therapeutic drug monitoring (TDM) guided dose optimisation could elucidate pharmacokinetic variabilities, improving treatment efficacy. However, detailed data on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for unbound ceftriaxone quantification in serum are scarce. Objective: The authors aimed to develop a reliable UPLC-MS/MS method for serum ceftriaxone quantification and exhibit its application potential in routine hospital settings. Methods: In this observational, single centre study, UPLC-MS/MS method validation included specificity, carry-over, linearity, repeatability, intermediate precision, accuracy, limit of quantification, and plasma protein binding. Unbound and total ceftriaxone were quantified in the serum of 5 critically ill patients. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment calculations were performed for both unbound and total ceftriaxone. The PK/PD target for unbound ceftriaxone in serum was set at 4 times the non-species related minimum inhibitory concentration breakpoint of 1 mg/L for at least 60% of the dosing interval. Result: The UPLC-MS/MS method revealed acceptable limits for clinical samples, with coefficients of variation < 15.0% for concentrations between 0.2 – 400.0 mg/L. Ceftriaxone eluted at 1.94 min and ceftazidime, as internal standard, eluted at 1.42 min. Patients demonstrated a median unbound ceftriaxone fraction of 29.1% (IQR: 15.2 – 52.2). Day 1 of ceftriaxone treatment presented a median PK/PD target attainment of 100.0% (IQR: 81.1 – 100.0) for unbound ceftriaxone in serum, while for calculations based on total concentrations, this figure was 23.9 % (IQR: 10.5 – 80.6). Conclusion: The described UPLC-MS/MS method enables reliable and rapid ceftriaxone quantification in the serum of critically ill patients. Method feasibility was exhibited for TDM purposes in routine clinical practice.

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