Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial)

José Molina, Clara María Rosso-Fernández, Enrique Montero-Mateos, José Ramón Paño-Pardo, María Solla, Ana Belén Guisado-Gil, Rocío Álvarez-Marín, María Eugenia Pachón-Ibáñez, Adelina Gimeno, Guillermo Martín-Gutiérrez, José Antonio Lepe, José Miguel Cisneros, SHORTEN-2 trial team, José Molina, Clara María Rosso-Fernández, Enrique Montero-Mateos, José Ramón Paño-Pardo, María Solla, Ana Belén Guisado-Gil, Rocío Álvarez-Marín, María Eugenia Pachón-Ibáñez, Adelina Gimeno, Guillermo Martín-Gutiérrez, José Antonio Lepe, José Miguel Cisneros, SHORTEN-2 trial team

Abstract

Background: Research priorities in Antimicrobial Stewardship (AMS) have rapidly evolved in the last decade. The need for a more efficient use of antimicrobials have fueled plenty of studies to define the optimal duration for antibiotic treatments, and yet, there still are large areas of uncertainty in common clinical scenarios. Pseudomonas aeruginosa has been pointed as a priority for clinical research, but it has been unattended by most randomized trials tackling the effectiveness of short treatments. The study protocol of the SHORTEN-2 trial is presented as a practical example of new ways to approach common obstacles for clinical research in AMS.

Objective: To determine whether a 7-day course of antibiotics is superior to 14-day schemes for treating bloodstream infections by P. aeruginosa (BSI-PA).

Methods: A superiority, open-label, randomized controlled trial will be performed across 30 Spanish hospitals. Adult patients with uncomplicated BSI-PA will be randomized to receive a 7 versus 14-day course of any active antibiotic. The primary endpoint will be the probability for the 7-day group of achieving better outcomes than the control group, assessing altogether clinical effectiveness, severe adverse events, and antibiotic exposure through a DOOR/RADAR analysis. Main secondary endpoints include treatment failure, BSI-PA relapses, and mortality. A superiority design was set for the primary endpoint and non-inferiority for treatment failure, resulting in a sample size of 304 patients.

Conclusions: SHORTEN-2 trial aligns with some of the priorities for clinical research in AMS. The implementation of several methodological innovations allowed overcoming common obstacles, like feasible sample sizes or measuring the clinical impact and unintended effects.

Trial registration: EudraCt: 2021-003847-10; ClinicalTrials.gov: NCT05210439.

Conflict of interest statement

The authors have declared that no competing interests exist.

Copyright: © 2022 Molina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Figures

Fig 1
Fig 1
Fig 2
Fig 2
Fig 3
Fig 3

References

    1. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet Lond Engl. 18 de enero de 2022;S0140-6736(21)02724-0.
    1. Review in Antimicrobial Resistance. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. 2014.
    1. Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al.. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. marzo de 2018;18(3):318–27.
    1. Bae M, Jeong Y, Bae S, Kim MJ, Chong YP, Kim S-H, et al.. Short versus prolonged courses of antimicrobial therapy for patients with uncomplicated Pseudomonas aeruginosa bloodstream infection: a retrospective study. J Antimicrob Chemother. 30 de septiembre de 2021;dkab358. doi: 10.1093/jac/dkab358
    1. Onorato L, Macera M, Calò F, Cirillo P, Caprio GD, Coppola N. Beta-lactam monotherapy or combination therapy for bloodstream infections or pneumonia due to P. aeruginosa: a meta-analysis. Int J Antimicrob Agents. 28 de diciembre de 2021;106512.
    1. Drusano GL, Louie A, MacGowan A, Hope W. Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1. Antimicrob Agents Chemother. 28 de diciembre de 2015;60(3):1183–93. doi: 10.1128/AAC.02177-15
    1. Morris AM, Calderwood MS, Fridkin SK, Livorsi DJ, McGregor JC, Mody L, et al.. Research needs in antibiotic stewardship. Infect Control Hosp Epidemiol. diciembre de 2019;40(12):1334–43.
    1. Bassetti M, Giacobbe DR, Vena A, Brink A. Challenges and research priorities to progress the impact of antimicrobial stewardship. Drugs Context. 19 de agosto de 2019;8:212600. doi: 10.7573/dic.212600
    1. Molina J, Montero-Mateos E, Praena-Segovia J, León-Jiménez E, Natera C, López-Cortés LE, et al.. Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 9 de septiembre de 2021;S1198-743X(21)00491-2.
    1. Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, et al.. Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial. Clin Infect Dis Off Publ Infect Dis Soc Am. 13 de septiembre de 2019;69(7):1091–8. doi: 10.1093/cid/ciy1054
    1. von Dach E, Albrich WC, Brunel A-S, Prendki V, Cuvelier C, Flury D, et al.. Effect of C-Reactive Protein-Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia: A Randomized Clinical Trial. JAMA. 2 de junio de 2020;323(21):2160–9. doi: 10.1001/jama.2020.6348
    1. Woudt SHS, de Greeff SC, Schoffelen AF, Vlek ALM, Bonten MJM. Antibiotic Resistance and the Risk of Recurrent Bacteremia. Clin Infect Dis Off Publ Infect Dis Soc Am. 1 de junio de 2018;66(11):1651–7. doi: 10.1093/cid/cix1076
    1. Bliziotis IA, Samonis G, Vardakas KZ, Chrysanthopoulou S, Falagas ME. Effect of Aminoglycoside and β-Lactam Combination Therapy versus β-Lactam Monotherapy on the Emergence of Antimicrobial Resistance: A Meta-analysis of Randomized, Controlled Trials. Clin Infect Dis. 15 de julio de 2005;41(2):149–58.
    1. Bernard L, Arvieux C, Brunschweiler B, Touchais S, Ansart S, Bru J-P, et al.. Antibiotic Therapy for 6 or 12 Weeks for Prosthetic Joint Infection. N Engl J Med. 27 de mayo de 2021;384(21):1991–2001.
    1. Cranendonk DR, Opmeer BC, van Agtmael MA, Branger J, Brinkman K, Hoepelman AIM, et al.. Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. mayo de 2020;26(5):606–12. doi: 10.1016/j.cmi.2019.09.019
    1. Llewelyn MJ, Hand K, Hopkins S, Walker AS. Antibiotic policies in acute English NHS trusts: implementation of «Start Smart-Then Focus» and relationship with Clostridium difficile infection rates. J Antimicrob Chemother. abril de 2015;70(4):1230–5.
    1. Bell S, Davey P, Nathwani D, Marwick C, Vadiveloo T, Sneddon J, et al.. Risk of AKI with gentamicin as surgical prophylaxis. J Am Soc Nephrol JASN. noviembre de 2014;25(11):2625–32. doi: 10.1681/ASN.2014010035
    1. Evans SR, Rubin D, Follmann D, Pennello G, Huskins WC, Powers JH, et al.. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis Off Publ Infect Dis Soc Am. 1 de septiembre de 2015;61(5):800–6.
    1. Schweitzer VA, van Werkhoven CH, Rodríguez Baño J, Bielicki J, Harbarth S, Hulscher M, et al.. Optimizing design of research to evaluate antibiotic stewardship interventions: consensus recommendations of a multinational working group. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. enero de 2020;26(1):41–50. doi: 10.1016/j.cmi.2019.08.017
    1. Cabellos C, Pelegrín I, Benavent E, Gudiol F, Tubau F, Garcia-Somoza D, et al.. Invasive meningococcal disease: Impact of short course therapy. A DOOR/RADAR study. J Infect. noviembre de 2017;75(5):420–5. doi: 10.1016/j.jinf.2017.08.009
    1. Celestin AR, Odom SR, Angelidou K, Evans SR, Coimbra R, Guidry CA, et al.. Novel Method Suggests Global Superiority of Short-Duration Antibiotics for Intra-abdominal Infections. Clin Infect Dis Off Publ Infect Dis Soc Am. 16 de octubre de 2017;65(9):1577–9. doi: 10.1093/cid/cix569
    1. EUCAST: Clinical breakpoints and dosing of antibiotics. 2022. .
    1. CONSORT 2010: Consolidated Standards of Reporting Trials [Internet]. [citado 10 de enero de 2022]. Disponible en:
    1. Molina J, Cisneros JM. A Chance to Change the Paradigm of Outcome Assessment of Antimicrobial Stewardship Programs. Clin Infect Dis Off Publ Infect Dis Soc Am. 25 de junio de 2015.
    1. Davey P, Marwick CA, Scott CL, Charani E, McNeil K, Brown E, et al.. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 9 de febrero de 2017;2:CD003543. doi: 10.1002/14651858.CD003543.pub4
    1. Rzewuska M, Charani E, Clarkson JE, Davey PG, Duncan EM, Francis JJ, et al.. Prioritizing research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. febrero de 2019;25(2):163–8. doi: 10.1016/j.cmi.2018.08.020
    1. Huttner A, Leibovici L, Theuretzbacher U, Huttner B, Paul M. Closing the evidence gap in infectious disease: point-of-care randomization and informed consent. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. febrero de 2017;23(2):73–7. doi: 10.1016/j.cmi.2016.07.029
    1. Harris PNA, McNamara JF, Lye DC, Davis JS, Bernard L, Cheng AC, et al.. Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. agosto de 2017;23(8):533–41. doi: 10.1016/j.cmi.2016.10.023
    1. Rahal JJ, Urban C, Horn D, Freeman K, Segal-Maurer S, Maurer J, et al.. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA. 1998;280(14):1233–7. doi: 10.1001/jama.280.14.1233
    1. Phillips PPJ, Morris TP, Walker AS. DOOR/RADAR: A Gateway Into the Unknown? Clin Infect Dis Off Publ Infect Dis Soc Am. 15 de marzo de 2016;62(6):814–5. doi: 10.1093/cid/civ1002
    1. Evans SR, Knutsson M, Amarenco P, Albers GW, Bath PM, Denison H, et al.. Methodologies for pragmatic and efficient assessment of benefits and harms: Application to the SOCRATES trial. Clin Trials Lond Engl. diciembre de 2020;17(6):617–26.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться