Impact of Real-Time Therapeutic Drug Monitoring on the Prescription of Antibiotics in Burn Patients Requiring Admission to the Intensive Care Unit

ABSTRACT As pharmacokinetics after burn trauma are difficult to predict, we conducted a 3-year prospective, monocentric, randomized, controlled trial to determine the extent of under- and overdosing of antibiotics and further evaluate the impact of systematic therapeutic drug monitoring (TDM) with same-day real-time dose adaptation to reach and maintain antibiotic concentrations within the therapeutic range. Forty-five consecutive burn patients treated with antibiotics were prospectively screened. Forty fulfilled the inclusion criteria; after one patient refused to participate and one withdrew consent, 19 were randomly assigned to an intervention group (patients with real-time antibiotic concentration determination and subsequent adaptations) and 19 were randomly assigned to a standard-of-care group (patients with antibiotic administration at the physician's discretion without real-time TDM). Seventy-three infection episodes were analyzed. Before the intervention, only 46/82 (56%) initial trough concentrations fell within the range. There was no difference between groups in the initial trough concentrations (adjusted hazard ratio = 1.39 [95% confidence interval {CI}, 0.81 to 2.39], P = 0.227) or the time to reach the target. However, thanks to real-time dose adjustments, the trough concentrations of the intervention group remained more within the predefined range (57/77 [74.0%] versus 48/85 [56.5%]; adjusted odd ratio [OR] = 2.34 [95% CI, 1.17 to 4.81], P = 0.018), more days were spent within the target range (193 days/297 days on antibiotics [65.0%] versus 171 days/311 days in antibiotics [55.0%]; adjusted OR = 1.64 [95% CI, 1.16 to 2.32], P = 0.005), and fewer results were below the target trough concentrations (25/118 [21.2%] versus 44/126 [34.9%]; adjusted OR = 0.47 [95% CI, 0.26 to 0.87], P = 0.015). No difference in infection outcomes was observed between the study groups. Systematic TDM with same-day real-time dose adaptation was effective in reaching and maintaining therapeutic antibiotic concentrations in infected burn patients, which prevented both over- and underdosing. A larger multicentric study is needed to further evaluate the impact of this strategy on infection outcomes and the emergence of antibiotic resistance during long-term burn treatment. (This study was registered with the ClinicalTrials.gov platform under registration no. NCT01965340 on 27 September 2013.)

[1]  Gabrielle Wilcox Infection prevention and treatment in patients with major burn injuries , 2010 .

[2]  M. Ansermino,et al.  Intensive care management and control of infection , 2004, BMJ : British Medical Journal.

[3]  J. Revelly,et al.  Antibiotic consumption to detect epidemics of Pseudomonas aeruginosa in a burn centre: A paradigm shift in the epidemiological surveillance of Pseudomonas aeruginosa nosocomial infections. , 2016, Burns : journal of the International Society for Burn Injuries.

[4]  L. Decosterd,et al.  Prospective Determination of Plasma Imipenem Concentrations in Critically Ill Children , 2006, Antimicrobial Agents and Chemotherapy.

[5]  F. Taccone,et al.  Therapeutic drug monitoring of anti-infective agents in critically ill patients , 2016, Expert review of clinical pharmacology.

[6]  J. Rello,et al.  Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: special emphasis on unbound pharmacokinetics. , 2010, The Journal of antimicrobial chemotherapy.

[7]  D. Bacquer,et al.  Development and validation of a model for prediction of mortality in patients with acute burn injury , 2009, The British journal of surgery.

[8]  P. Dziewulski,et al.  Cause of death and correlation with autopsy findings in burns patients. , 2013, Burns : journal of the International Society for Burn Injuries.

[9]  D. Nicolau,et al.  Pharmacokinetics of Doripenem in Infected Patients Treated Within and Outside the Intensive Care Unit , 2013, The Annals of pharmacotherapy.

[10]  E. Alp,et al.  Risk Factors for Nosocomial Infection and Mortality in Burn Patients: 10 Years of Experience at a University Hospital , 2012, Journal of burn care & research : official publication of the American Burn Association.

[11]  J. Bartlett,et al.  Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  J. Revelly,et al.  Staphylococcus aureus carriage at admission predicts early-onset pneumonia after burn trauma , 2016, European Journal of Clinical Microbiology & Infectious Diseases.

[13]  A. Shorr,et al.  Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients , 2013, Critical Care.

[14]  A. Boyer,et al.  Pseudomonas aeruginosa acquisition on an intensive care unit: relationship between antibiotic selective pressure and patients' environment , 2011, Critical care.

[15]  Ronald N. Jones,et al.  10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[16]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[17]  M. Lesseva Central venous catheter-related bacteraemia in burn patients. , 1998, Scandinavian journal of infectious diseases.

[18]  R. Boots,et al.  ARC--augmented renal clearance. , 2011, Current pharmaceutical biotechnology.

[19]  R. Salisbury Development and validation of a model for prediction of mortality in patients with acute burn injury , 2010 .

[20]  S. Harbarth,et al.  Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for? , 2015, The Journal of antimicrobial chemotherapy.

[21]  M. Roberts,et al.  An international, multicentre survey of β-lactam antibiotic therapeutic drug monitoring practice in intensive care units. , 2014, The Journal of antimicrobial chemotherapy.

[22]  Alexander A. Morgan,et al.  Prediction of Multiple Infections After Severe Burn Trauma , 2015 .

[23]  R. Gamelli,et al.  Ten year experience of burn, trauma, and combined burn/trauma injuries comparing outcomes. , 2004, The Journal of trauma.

[24]  R. Gamelli,et al.  Morbidity and Survival Probability in Burn Patients in Modern Burn Care* , 2015, Critical care medicine.

[25]  J. Roberts,et al.  β-Lactam therapeutic drug monitoring in the critically ill: optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia. , 2013, International journal of antimicrobial agents.

[26]  J. Rello,et al.  The Effects of Hypoalbuminaemia on Optimizing Antibacterial Dosing in Critically Ill Patients , 2011, Clinical pharmacokinetics.

[27]  D. Paterson,et al.  Therapeutic Drug Monitoring of Beta-Lactam Antibiotics in Burns Patients—A One-Year Prospective Study , 2012, Therapeutic drug monitoring.

[28]  D. Smith,et al.  Effect of inhalation injury, burn size, and age on mortality: a study of 1447 consecutive burn patients. , 1994, The Journal of trauma.

[29]  A. Šimek,et al.  Antimicrobial agents , 2008, Folia Microbiologica.

[30]  V. Briedis,et al.  Augmented renal clearance – an evolving risk factor to consider during the treatment with vancomycin , 2013, Journal of clinical pharmacy and therapeutics.

[31]  M. Kollef,et al.  Antibiotic stewardship in the intensive care unit. , 2011, Seminars in respiratory and critical care medicine.

[32]  M. Berger,et al.  Standardizing the diagnosis of inhalation injury using a descriptive score based on mucosal injury criteria. , 2012, Burns : journal of the International Society for Burn Injuries.

[33]  L. Decosterd,et al.  Impact of the introduction of real-time therapeutic drug monitoring on empirical doses of carbapenems in critically ill burn patients. , 2015, Burns : journal of the International Society for Burn Injuries.

[34]  K. Colpaert,et al.  Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. , 2013, Journal of critical care.

[35]  D. Church,et al.  Burn Wound Infections , 2006, Clinical Microbiology Reviews.

[36]  G. Rowley-Conwy,et al.  Infection prevention and treatment in patients with major burn injuries. , 2010, Nursing standard (Royal College of Nursing (Great Britain) : 1987).

[37]  J. Minei,et al.  Inflammation and the Host Response to Injury, a Large-Scale Collaborative Project: patient-oriented research core--standard operating procedures for clinical care. II. Guidelines for prevention, diagnosis and treatment of ventilator-associated pneumonia (VAP) in the trauma patient. , 2006, The Journal of trauma.

[38]  M. Berger,et al.  Prospective monitoring of cefepime in intensive care unit adult patients , 2011 .

[39]  K. Colpaert,et al.  Outcome and changes over time in survival following severe burns from 1985 to 2004 , 2005, Intensive Care Medicine.

[40]  C. Ryan,et al.  Objective estimates of the probability of death from burn injuries. , 1998, The New England journal of medicine.

[41]  U. Tröger,et al.  Intravenous colistin in a patient with serious burns and borderline syndrome: the benefits of therapeutic drug monitoring. , 2013, International journal of antimicrobial agents.

[42]  A. Telenti,et al.  14. Antimicrobial Agents , 2012 .

[43]  J. Roberts,et al.  How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients? , 2014, BMC Infectious Diseases.