Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper #

Author(s): Mohd H. Abdul-Aziz ¹ , Jan-Willem C. Alffenaar ² ^, ³ ^, ⁴ , Matteo Bassetti ⁵ , Hendrik Bracht ⁶ , George Dimopoulos ⁷ , Deborah Marriott ⁸ , Michael N. Neely ⁹ ^, ¹⁰ , Jose-Artur Paiva ¹¹ ^, ¹² , Federico Pea ¹³ , Fredrik Sjovall ¹⁴ , Jean F. Timsit ¹⁵ ^, ¹⁶ , Andrew A. Udy ¹⁷ ^, ¹⁸ , Sebastian G. Wicha ¹⁹ , Markus Zeitlinger ²⁰ , Jan J. De Waele ²¹ , Jason A. Roberts ¹ ^, ²² ^, ²³ ^, ²⁴ ^, , the Infection Section of European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Group of International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), Infections in the ICU and Sepsis Working Group of International Society of Antimicrobial Chemotherapy (ISAC)

Publication date (Electronic): 7 May 2020

Journal: Intensive Care Medicine

Publisher: Springer Berlin Heidelberg

Keywords: Antibacterials, Antifungals, Antivirals, Pharmacokinetics, Pharmacodynamics, Sepsis

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Abstract

Purpose

This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.

Methods

Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes.

Results

TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients.

Conclusion

Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide.

Electronic supplementary material

The online version of this article (10.1007/s00134-020-06050-1) contains supplementary material, which is available to authorized users.

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Most cited references 224

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DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?

Jason A Roberts, Sanjoy K Paul, Murat Akova … (2014)

Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.

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Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.

Saskia Bolay, Thierry Calandra, Jacques Bille … (2008)

Voriconazole is the therapy of choice for aspergillosis and a new treatment option for candidiasis. Liver disease, age, genetic polymorphism of the cytochrome CYP2C19, and comedications influence voriconazole metabolism. Large variations in voriconazole pharmacokinetics may be associated with decreased efficacy or with toxicity. This study was conducted to assess the utility of measuring voriconazole blood levels with individualized dose adjustments. A total of 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A large variability in voriconazole trough blood levels was observed, ranging from 5.5 mg/L (a level possibly associated with toxicity) in 31% of cases. Lack of response to therapy was more frequent in patients with voriconazole levels 1 mg/L (15 [12%] of 39 patients; P=.02). Blood levels >1 mg/L were reached after increasing the voriconazole dosage, with complete resolution of infection in all 6 cases. Among 16 patients with voriconazole trough blood levels >5.5 mg/L, 5 patients (31%) presented with an encephalopathy, including 4 patients who were treated intravenously with a median voriconazole dosage of 8 mg/kg per day, whereas none of the patients with levels

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Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.

J Paladino, J Schentag, Karen P. McKinnon (2008)

The objective of this study was to evaluate the relationship of the predicted pharmacodynamic parameters 24-h area under the inhibitory curve (AUIC=area under the concentration-time curve for 24h of dosing/minimum inhibitory concentration (AUC0-24/MIC) and time above the minimum inhibitory concentration (T>MIC) with clinical and microbiological outcomes in patients with bacteraemia and sepsis treated with cefepime or ceftazidime. Pharmacokinetic and pharmacodynamic parameters were derived for 76 of 107 patients enrolled in two prospective, randomised, clinical trials comparing cefepime with ceftazidime for the treatment of sepsis with bacteraemia, lower respiratory tract infection or complicated urinary tract infection. The relationships between the pharmacodynamic parameters and outcomes were examined. Whilst no significant differences in clinical outcomes were observed between cefepime and ceftazidime, there were significant differences in the pharmacodynamic analysis. Patients with an AUIC> or =250 had significantly greater clinical cure (79% vs. 33%; P=0.002) and bacteriological eradication (96% vs. 44%; P MIC of 100% had significantly greater clinical cure (82% vs. 33%; P=0.002) and bacteriological eradication (97% vs. 44%; P MIC of MIC was <100%.

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Author and article information

Contributors

Jason A. Roberts: j.roberts2@uq.edu.au

Journal

Journal ID (nlm-ta): Intensive Care Med

Journal ID (iso-abbrev): Intensive Care Med

Title: Intensive Care Medicine

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0342-4642

ISSN (Electronic): 1432-1238

Publication date (Electronic): 7 May 2020

Pages: 1-27

Affiliations

[1 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, , The University of Queensland, ; Brisbane, QLD 4029 Australia

[2 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, School of Pharmacy, Faculty of Medicine and Health, , University of Sydney, ; Sydney, NSW Australia

[3 ]GRID grid.413252.3, ISNI 0000 0001 0180 6477, Westmead Hospital, ; Westmead, NSW Australia

[4 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, Marie Bashir Institute of Infectious Diseases and Biosecurity, , University of Sydney, ; Sydney, NSW Australia

[5 ]GRID grid.5606.5, ISNI 0000 0001 2151 3065, Infectious Diseases Clinic, Department of Health Sciences, , University of Genoa, Genoa and Hospital Policlinico San Martino – IRCCS, ; Genoa, Italy

[6 ]GRID grid.6582.9, ISNI 0000 0004 1936 9748, Department of Anaesthesiology, , University Ulm, ; Ulm, Germany

[7 ]GRID grid.5216.0, ISNI 0000 0001 2155 0800, Department of Critical Care, University Hospital Attikon, , National and Kapodistrian University of Athens, ; Athens, Greece

[8 ]GRID grid.437825.f, ISNI 0000 0000 9119 2677, Department of Microbiology and Infectious Diseases, , St. Vincent’s Hospital, ; Sydney, NSW Australia

[9 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, Department of Paediatrics, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA USA

[10 ]GRID grid.239546.f, ISNI 0000 0001 2153 6013, Division of Infectious Diseases, , Children’s Hospital Los Angeles, ; Los Angeles, CA USA

[11 ]GRID grid.5808.5, ISNI 0000 0001 1503 7226, Department of Medicine, , Faculty of Medicine of Porto, ; Porto, Portugal

[12 ]Department of Emergency and Intensive Care Medicine, Centro Hospitalar Universitario de São João, Porto, Portugal

[13 ]Institute of Clinical Pharmacology, SM Misericordia University Hospital, ASUFC, Udine, Italy

[14 ]GRID grid.411843.b, ISNI 0000 0004 0623 9987, Department of Perioperative Medicine, , Skåne University Hospital, ; Malmö, Sweden

[15 ]Department of Intensive Care Medicine and Infectious Diseases, Bichat-Claude Bernard University Hospital, AP-HP, Paris, France

[16 ]GRID grid.7452.4, ISNI 0000 0001 2217 0017, Infection, Antimicrobials, Modelling, Evolution (IAME), , Paris Diderot University, ; Paris, France

[17 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, , Monash University, ; Melbourne, VIC Australia

[18 ]GRID grid.1623.6, ISNI 0000 0004 0432 511X, Department of Intensive Care and Hyperbaric Medicine, , The Alfred, ; Melbourne, VIC Australia

[19 ]GRID grid.9026.d, ISNI 0000 0001 2287 2617, Department of Clinical Pharmacy, Institute of Pharmacy, , University of Hamburg, ; Hamburg, Germany

[20 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Department of Clinical Pharmacology, , Medical University of Vienna, ; Vienna, Austria

[21 ]GRID grid.410566.0, ISNI 0000 0004 0626 3303, Department of Critical Care Medicine, , Ghent University Hospital, ; Ghent, Belgium

[22 ]GRID grid.416100.2, ISNI 0000 0001 0688 4634, Department of Intensive Care Medicine and Pharmacy, , Royal Brisbane and Women’s Hospital, ; Brisbane, QLD Australia

[23 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, , The University of Queensland, ; Brisbane, QLD Australia

[24 ]GRID grid.121334.6, ISNI 0000 0001 2097 0141, Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, , University of Montpellier, ; Nîmes, France

Article

Publisher ID: 6050

DOI: 10.1007/s00134-020-06050-1

PMC ID: 7223855

PubMed ID: 32383061

SO-VID: ba89b6bd-4e16-4b2a-be03-758d88aa2746

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

History

Date received : 30 January 2020

Date accepted : 10 April 2020

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Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper _#

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Abstract

Purpose

Methods

Results

Conclusion

Electronic supplementary material

Related collections

Irish Journal of Paramedicine

Most cited references 224

DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?

Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.

Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.

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Cited by 232

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