Health Care Costs of Target Attainment for Beta-Lactam Antibiotics in Critically Ill Patients

Abstract Background Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment. Methods This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MICECOFF and ƒT > 4×MICECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes. Results A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MICECOFF and 36.7% achieved 100%ƒT > 4×MICECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2, and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival. Conclusions Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Trial registration Netherlands Trial Registry (EXPAT trial), NTR 5632. Registered on 7 December 2015.

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Prolonged Infusion of Beta-lactam Antibiotics in Critically Ill Patients: Revisiting the Evidence

Annual Update in Intensive Care and Emergency Medicine 2018 - Annual Update in Intensive Care and Emergency Medicine ◽

10.1007/978-3-319-73670-9_5 ◽

2018 ◽

pp. 53-69

Author(s):

S. A. M. Dhaese ◽

V. Stove ◽

J. J. De Waele

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Beta Lactam ◽

Prolonged Infusion ◽

Beta Lactam Antibiotics

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Optimization of the treatment with beta-lactam antibiotics in critically ill patients—guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique—SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d’Anesthésie et Réanimation—SFAR)

Critical Care ◽

10.1186/s13054-019-2378-9 ◽

2019 ◽

Vol 23 (1) ◽

Cited By ~ 49

Author(s):

Romain Guilhaumou ◽

Sihem Benaboud ◽

Youssef Bennis ◽

Claire Dahyot-Fizelier ◽

Eric Dailly ◽

...

Keyword(s):

Intensive Care ◽

Intensive Care Medicine ◽

Critically Ill ◽

Critically Ill Patients ◽

Beta Lactam ◽

French Society ◽

Beta Lactam Antibiotics

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The higher the better? Defining the optimal beta-lactam target for critically ill patients to reach infection resolution and improve outcome

Journal of Intensive Care ◽

10.1186/s40560-020-00504-w ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Christina Scharf ◽

Uwe Liebchen ◽

Michael Paal ◽

Max Taubert ◽

Michael Vogeser ◽

...

Keyword(s):

Liver Function ◽

Hospital Mortality ◽

Critically Ill ◽

Critically Ill Patients ◽

Beta Lactam ◽

Target Attainment ◽

Outcome Group ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Objectives Beta-lactam antibiotics are often subject to therapeutic drug monitoring, but breakpoints of target attainment are mostly based on expert opinions. Studies that show a correlation between target attainment and infection resolution are missing. This analysis investigated whether there is a difference in infection resolution based on two breakpoints of target attainment. Methods An outcome group out of 1392 critically ill patients treated with meropenem or piperacillin-tazobactam was formed due to different selection criteria. Afterwards, three groups were created: group 1=free drug concentration (f) was < 100% of the time (T) above the minimal inhibitory concentration (MIC) (< 100% fT >MIC), group 2=100% fT >MIC<4xMIC, and group 3=100% fT >4xMIC. Parameters for infection control, renal and liver function, and estimated and observed in-hospital mortality were compared between those groups. Statistical analysis was performed with one-way analysis of variance, Tukey post hoc test, U test, and bivariate logistic regression. Results The outcome group consisted of 55 patients (groups 1–3, 17, 24, and 14 patients, respectively). Patients allocated to group 2 or 3 had a significantly faster reduction of the C-reactive protein in contrast to patients allocated to group 1 (p = 0.033 and p = 0.026). Patients allocated to group 3 had a worse renal function, a higher Acute Physiology and Chronic Health Evaluation (APACHE II) score, were older, and had a significantly higher in-hospital mortality compared to group 1 (p = 0.017) and group 2 (p = 0.001). The higher mortality was significantly influenced by worse liver function, higher APACHE II, and higher Sequential Organ Failure Assessment (SOFA) score and norepinephrine therapy. Conclusion Achieving the target 100% fT >MIC leads to faster infection resolution in the critically ill. However, there was no benefit for patients who reached the highest target of 100% fT >4xMIC, although the mortality rate was higher possibly due to confounding effects. In conclusion, we recommend the target 100% fT >MIC<4xMIC for critically ill patients. Trial registration NCT03985605

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

Antibiotics ◽

10.3390/antibiotics9030131 ◽

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.

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Pharmacodynamic Target Attainment for Cefepime, Meropenem, and Piperacillin-Tazobactam Using a Pharmacokinetic/Pharmacodynamic-Based Dosing Calculator in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01008-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 9

Author(s):

Emily L. Heil ◽

David P. Nicolau ◽

Andras Farkas ◽

Jason A. Roberts ◽

Kerri A. Thom

Keyword(s):

Prospective Study ◽

Critically Ill ◽

Critically Ill Patients ◽

Package Insert ◽

Beta Lactam ◽

Target Attainment ◽

A Prospective Study ◽

Antibiotic Dosing

ABSTRACT This was a prospective study to determine if pharmacokinetic/pharmacodynamic (PK/PD)-based antibiotic dosing software aids in achieving concentration targets in critically ill patients receiving cefepime (n = 10), meropenem (n = 20), or piperacillin-tazobactam (n = 19). Antibiotic calculator doses targeting a >90% probability of target attainment (PTA) differed from package insert doses for 22.4% (11/49) of patients. Target attainment was achieved for 98% of patients (48/49). A PK/PD-based antibiotic dosing calculator provides beta-lactam doses with a high PTA in critically ill patients.

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Continuous Infusion Compared with Intermittent Intravenous Infusion of Beta-Lactam Antibiotics for Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Trials

10.21203/rs.3.rs-83282/v1 ◽

2020 ◽

Author(s):

Chien-Huei Huang ◽

Ching-Yao Shih ◽

Meng Keng Tsay ◽

Shen-Pei Hsuan ◽

Yung-Hsin Tseng ◽

...

Keyword(s):

Continuous Infusion ◽

Critically Ill ◽

Critically Ill Patients ◽

Eradication Rate ◽

Cochrane Library ◽

Secondary Outcome ◽

Bacterial Eradication ◽

Beta Lactam ◽

Beta Lactams ◽

Beta Lactam Antibiotics

Abstract Background: The pathophysiologic changes during critical illness and high minimal inhibitory concentration (MIC) pathogens are important risk factors of mortality and bacterial eradication in critical care. Beta-lactam antibiotics have a time-dependent effect on bactericidal activity. The continuous infusion (CIF) of beta-lactam antibiotics achieves sufficient drug concentration above the MIC, especially for critically ill patients. However, the superiority of CIF over intermittent infusion (IIF) of beta-lactam antibiotics is yet to be clearly established. Thus, we aimed to investigate the effects on mortality of CIF of beta-lactams antibiotics in comparison to those of IIF of beta-lactams antibiotics in patients with sepsis admitted to the intensive care unit (ICU).Methods: We systematically searched PUBMED, MEDLINE, Cochrane Library, EMBASE, Web of Science, and ICTRP for randomized controlled trials (RCTs) comparing CIF with IIF of beta-lactam antibiotics in critically ill populations. All RCTs published until October 2019 were eligible. The primary outcome measure was the relative risk (RR) of mortality, while the secondary outcome measures were bacterial eradication rate, length of ICU stay, and length of admission. Results: In total, 6 RCTs comprising 974 patients were analyzed. We found a significantly lower mortality for critically ill patients on CIF (RR: 0.79; 95% CI: 0.63, 0.98) compared with those on IIF of beta-lactam antibiotics. The pooled RR for the bacterial eradication rate was 1.16 (95% CI: 1.03, 1.29) for CIF compared with IIF administration. Conclusion: CIF of beta-lactam antibiotics for critically ill patients significantly reduces mortality and yields a better bacterial eradication rate than IIF. These findings support the clinical and bacterial eradication benefits in adult critically ill patients, and may guide clinical discussions and decisions.

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Conceptual model of adding antibiotics to dialysate fluid during renal replacement therapy

Scientific Reports ◽

10.1038/s41598-021-03450-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ieva Bartuseviciene ◽

Vaidas Vicka ◽

Alvita Vickiene ◽

Lidija Tetianec ◽

Marius Dagys ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Replacement Therapy ◽

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Beta Lactam ◽

Antibiotic Concentration ◽

Experimental Conditions ◽

Beta Lactam Antibiotics ◽

Dialysate Solution

AbstractStudies have shown significant variability in antibiotic trough concentrations in critically ill patients receiving renal replacement therapy (RRT). The purpose of this study was to assess whether adding beta-lactam antibiotics to dialysate solution can maintain stable antibiotic concentrations during RRT in experimental conditions. A single compartment model reflecting the patient was constructed and connected to the RRT machine. Dialysate fluid was prepared in three different concentrations of meropenem (0 mg/L; 16 mg/L; 64 mg/L). For each dialysate concentration various combinations of dialysate and blood flow rates were tested by taking different samples. Meropenem concentration in all samples was calculated using spectrophotometry method. Constructed experimental model results suggest that decrease in blood meropenem concentration can be up to 35.6%. Moreover, experimental data showed that antibiotic loss during RRT can be minimized and stable plasma antibiotic concentration can be achieved with the use of a 16 mg/L Meropenem dialysate solution. Furthermore, increasing meropenem concentration up to 64 mg/L is associated with an increase antibiotic concentration up to 18.7–78.8%. Administration of antibiotics to dialysate solutions may be an effective method of ensuring a constant concentration of antibiotics in the blood of critically ill patients receiving RRT.

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