Stop Antibiotics on guidance of Procalcitonin Study (SAPS): a randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients - calculated sample size: 1816 patients

BMC Infectious Diseases

Albertus Beishuizen³  Jos W Twisk¹  Maarten W Nijsten⁵  Jos A van Oers⁶  Dylan W de Lange²  Evelien Assink-de Jong⁴ 

[1] Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Boelelaan 1117, Amsterdam, 1081 HV, Netherlands;Department of Intensive Care and Emergency Medicine, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, Netherlands;Department of Intensive Care, Medisch Spectrum Twente, Haaksbergerstraat 55, Enschede, 7513 ER, Netherlands;Department of Intensive Care, VU University Medical Center, Boelelaan 1117, Amsterdam, 1081 HV, Netherlands;Department of Critical Care, University Medical Center Groningen, Hanzeplein 1, Groningen, 9700 RB, Netherlands;Department of Intensive Care, St. Elisabeth Hospital Tilburg, Hilvarenbeekseweg 60, Tilburg, 5022 GC, Netherlands

关键词: Septic shock;    Sepsis;    Procalcitonin;    Intensive care unit;    Defined daily dosage;    C-reactive protein;    Critical illness;    Biomarker;    Antibiotic duration;    Antibiotics;   

Others  :  1148865
DOI  :  10.1186/1471-2334-13-178

 received in 2012-07-22, accepted in 2013-03-26,  发布年份 2013

【 摘 要 】

Background

Unnecessary long-term use of broad-spectrum antibiotics is linked to the emergence and selection of resistant bacteria, prolonged hospitalisation and increased costs. Several clinical trials indicate that the biomarker procalcitonin (PCT) can guide antibiotic therapy. Some of these trials have shown a promising reduction in the number of antibiotic prescriptions, duration of antibiotic therapy and even length of stay in the ICU, although their size and selection criteria limit their external validity. The objectives of the Stop Antibiotics on guidance of Procalcitonin Study (SAPS) are to evaluate whether daily PCT can improve “real-life” antibiotic use in Dutch ICU’s by reduction of the duration of antibiotic treatment without an increase of recurrent infections and mortality.

Methods/Design

Multicenter randomised controlled intervention trial. Powered for superiority of the primary efficacy endpoint and non-inferiority on the primary safety endpoints (non-inferiority margin is set on 8%).

Inclusion criteria: (1) ICU-patients aged ≥18 years and (2) receiving antibiotics for a presumed or proven infection and (3) signed informed consent. Exclusion criteria: (1) patients who require prolonged antibiotic therapy, (2) suffer from Mycobacterium tuberculosis, (3) cystic fibrosis, (4) viral or parasitic infections and (5) those that are severely immunocompromised or (6) moribund.

The intervention consists solely of an advice to discontinue antibiotic treatment in case PCT has decreased by more than 80% of its peak level (relative stopping threshold) or decrease below a value of 0.5 ng/ml (absolute stopping threshold).

The study hypothesis is that PCT-guided therapy is non-inferior to standard care based on implemented guidelines and local expertise, whilst reducing antibiotic usage. Computerised 1:1 randomisation will allocate 908 patients per arm. Arm 1: standard of care. Arm 2: procalcitonin-guided therapy. The primary efficacy endpoint is consumption of antibiotics expressed as the defined daily dosage and duration of antibiotic therapy expressed in days of therapy. This trial is designed to shorten antibiotics safely, therefore the primary safety endpoint is mortality measured at 28 day and 1 year.

Discussion

This will be the largest procalcitonin-guided antibiotic intervention trial in ICU setting thus far. Currently 1600 of the planned 1816 patients are randomised (November 2012). The first interim analysis has passed without any safety or futility issues.

Trial registration

Trial registration number at http://www.clinicaltrials.gov webcite: Id. Nr. NCT01139489 , at http://www.trialregister.nl webcite: Id.nr. NTR1861.

【 授权许可】

   
2013 Assink-de Jong et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]The bacterial challenge: time to react, Joint Technical Report from ECDC and EMA, Stockholm, September 2009.
• [2]Evans HL, Lefrak SN, Lyman J, Smith RL, Chong TW, McElearney ST, Schulman AR, Hughes MG, Raymond DP, Sawyer RG: Cost of gram-negative resistance. Crit Care Med 2007, 35:89-95.
• [3]Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands. Stichting Werkgroep Antibiotica Beleid in collaboration with the RIVM. NethMap 2011.
• [4]Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands. Stichting Werkgroep Antibiotica Beleid in collaboration with the RIVM. NethMap 2008.
• [5]Kumar A, Roberts D, Wood KE, Light B, Parillo JE, Sharma S, Suppes R, Fenstein D, Zanotti S, Talberg L, Gurka D, Kumar A, Cheang M: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006, 34:1589-1596.
• [6]Becker KL, Snider R, Nylen ES: Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 2008, 36(3):941-952.
• [7]Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C: High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993, 341:515-518.
• [8]Schroeder S, Hochreiter M, Koehler T, Schweiger AM, Bein B, Keck FS, von Spiegel T: Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Langenbecks Arch Surg 2009 Mar, 394(2):221-226.
• [9]Muller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR, Zimmerli W, Ritz R: Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med 2000, 28:977-983.
• [10]O’Grady NP, Barie PS, Bartlett JG, Bleck T, Caroll K, Kalil AC, Maki DG, Nierman D, Pasculle W, Masur H: Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical care Medicine and the Infectious Diseases Society of America. Crit Care Med 2008, 36:1330-1344.
• [11]Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, Muller B: Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004, 363(9409):600-607.
• [12]Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, Zimmerli W, Harbarth S, Tamm M, Muller B: Procalcitonin Guidance of Antibiotic Therapy in Community-acquired Pneumonia: A Randomized Trial. Am J Respir Crit Care Med 2006, 174:84-93.
• [13]Stolz D, Christ-Crain M, Bingisser R, Leuppi J, Miedinger D, Muller C, Huber P, Muller B, Tamm M: Antibiotic Treatment of Exacerbations of COPD: A Randomized, Controlled Trial Comparing Procalcitonin-Guidance With Standard Therapy. Chest 2007, 131:9-19.
• [14]Schuetz P, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, Luyt CE, Chastre J, Tubach F, Kristoffersen KB, Wei L, Burkhardt O, Welte T, Schroeder S, Nobre V, Tamm M, Bhatnagar N, Bucher HC, Mueller B: Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis 2012 Sep, 55(5):651-662.
• [15]Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J: Use of Procalcitonin to Shorten Antibiotic Treatment Duration in Septic Patients. A Randomized Trial. Am J Respir Crit Care Med 2008, 177:498-505.
• [16]Hochreiter M, Köhler T, Schweiger AM, Keck FS, Bein B, Von Spiegel T, Schroeder S: Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care 2009, 13:R83. BioMed Central Full Text
• [17]Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, Schortgen F, Lasocki S, Veber B, Dehoux M, Bernhard M, Pasquet B, Regnier B, Brun-Buisson C, Chastre J, Wolff M: Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010, 375:463-474.
• [18]Stolz D, Smyrnios N, Eggimann P, Pargger H, Thakkar N, Siegemund M, Marsch S, Azzola A, Rakic J, Mueller B, Tamm M: Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J 2009, 34:1364-1375.
• [19]Svoboda P, Kantorová I, Scheer P, Radvanova J, Radvan M: Can procalcitonin help us in timing of reintervention in septic patients after multiple trauma or major surgery? Hepatogastroenterology 2007, 54:359-363.
• [20]De Kruif MD, Lemaire LC, Giebelen IA, Struck J, Morgenthaler NG, Papassotiriou J, Elliott PJ, Van der Poll T: The influence of corticosteroids on the release of novel biomarkers in human endotoxemia. Intensive Care Med 2008, 34:518-522.
• [21]Pocock SJ: Group sequential methods in the design and analysis of clinical trials. Biometrika 1977, 64(2):191-199.
• [22]Jensen JU, Hein L, Lundgren B, Procalcitonin And Survival Study (PASS) Group, et al.: Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med 2011, 39(9):2048-2058.
• [23]Matthaiou DK, Ntani G, Kontogiorgi M, Poulakou G, Armaganidis A, Dimopoulos G: An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients. Intensive Care Med 2012, 38(6):940-949.
• [24]Schuetz P, Chiappa V, Briel M, Greenwald JL: Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011, 171(15):1322-1331.
• [25]Heyland DK, Johnson AP, Reynolds SC, Muscedere J: Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation. Crit Care Med 2011, 39:1792-1799.
• [26]Kopterides P, Siempos II, Tsangaris I, Tsantes A, Armaganidis A: Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med 2010, 38(11):2229-2241.
• [27]Tang BM, Eslick GD, Craig JC, McLean AS: Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis 2007, 7(3):210-217.
• [28]Kollef MH: Will procalcitonin reduce antibiotic use in intensive care ? Lancet 2010, 375(9713):435-436.
• [29]Meijvis SC, Hardeman H, Remmelts HH, Heijligenberg R, Rijkers GT, van Velzen-Blad H, Voorn GP, van de Garde EM, Endeman H, Grutters JC, Bos WJ, Biesma DH: Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet 2011, 377(9782):2023-2030.