Therapeutic Monitoring of Beta-lactams in Critically Ill Patients With Sepsis

NCT07270523 | Not Yet Recruiting

• 1 other identifier: OPTIBETA
• Study Type: interventional
• Target: 198
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Sepsis is a leading cause of morbidity and mortality among critically ill patients and is associated with intensive use of β-lactam antibiotics. These drugs show time-dependent pharmacodynamics and high pharmacokinetic variability in this population, making it difficult to achieve therapeutic levels. Therapeutic drug monitoring (TDM) may optimize dosing, but its routine clinical implementation remains limited. Objective: To evaluate whether individualized β-lactam dosing guided by TDM reduces time to full clinical recovery compared with standard dosing in critically ill patients with sepsis. Methods: OPTIBETA is a pragmatic, randomized, controlled, open-label clinical trial to be conducted at a tertiary hospital in Spain. Adult patients (≥18 years) admitted to the intensive care unit or infectious diseases ward with sepsis will be included. Participants will be randomized 1:1 to either a TDM-guided dosing arm (dose adjustments according to PK/PD targets) or a standard dosing arm. Clinical, microbiological, and pharmacological outcomes will be collected. The primary endpoint is time to complete clinical cure. Secondary outcomes include overall survival, microbiological cure, ICU and hospital length of stay, adverse events, and achievement of PK/PD targets. The estimated sample size is 198 patients. Expected results: We hypothesize that TDM-guided dosing will reduce time to clinical cure, improve overall outcomes, and decrease adverse events compared with standard dosing. Conclusions: OPTIBETA will provide high-quality evidence on the role of β-lactam TDM in critically ill septic patients and may support its inclusion in antimicrobial stewardship programs.

Conditions

Bacterial Sepsis

Keywords

betalactam; therapeutic drug monitoring; sepsis; clinical cure; microbiological cure

Outcome Measures

Primary Outcomes (1)

• Time to complete clinical cure

  The primary endpoint will be the time to complete clinical cure, defined as resolution of signs and symptoms of infection, functional recovery, baseline or improved SOFA score (≥2 points from baseline), and no need to initiate new antibiotic treatment.

  From the date of randomization to the date of clinical cure, assessed every 7 days and until the end of the study, an average of 3 years.

Secondary Outcomes (9)

• Time to microbiological cure (negative cultures).

  From the date of randomization to the date of microbiological cure, assessed every 7 days and until the end of the study, an average of 3 years

• Overall survival (OS)

  From the start date of treatment until the end of the study, an average of 3 years.

• Length of hospital stay

  From the date of randomization until the end of the study, an average of 3 years.

• Number of days free of life support

  From the date of randomization until the end of the study, an average of 3 years.

• Security

  From the start date of treatment until the end of the study, an average of 3 years.

Study Arms (2)

Intervention group (individualized dosing based on therapeutic monitoring)

EXPERIMENTAL

Patients will receive individualized dosing of beta-lactam antibiotics based on therapeutic monitoring. Total and free plasma concentrations will be determined 48 hours after the start of antibiotic therapy and subsequently every 4-5 days, or sooner if there is a significant clinical change. Dosage adjustments will be made to achieve the defined PK/PD targets: * Standard: ≥100% fT \> MIC. * Infections caused by multidrug-resistant pathogens, increased renal clearance, or immunosuppression: ≥100% fT \> 4×MIC. Concentrations will be interpreted in relation to the actual MIC of the identified pathogen or, failing that, to the ECOFF values defined by EUCAST.

Other: Individualized dosing of beta-lactam antibiotics based on therapeutic monitoring

Control group (usual dosage):

NO INTERVENTION

Patients will receive the usual dosage of beta-lactam antibiotics following the recommendations of clinical guidelines and hospital protocols, without individualized adjustment based on MDT. Plasma samples will also be collected, but will be stored for deferred analysis at the end of the study, with no impact on clinical management.

Interventions

Individualized dosing of beta-lactam antibiotics based on therapeutic monitoring OTHER

In the intervention group, plasma levels will be determined 48 hours after the start of antibiotic treatment and subsequently every 4-5 days, with a pharmacotherapeutic report and dosage adjustment within \<24 hours. In the control group, samples will be stored at -80 °C and analyzed at the end of the study, with no impact on clinical practice. Plasma concentrations of beta-lactam antibiotics will be determined by high-performance liquid chromatography (HPLC) using validated commercial kits, which allow simultaneous quantification of several drugs in this group with reduced processing times and feasible implementation in hospital routine. Patients will be evaluated weekly until hospital discharge, death, or completion of antibiotic treatment. Clinical progression, inflammatory markers, emergence of resistance, adverse effects, and clinical and microbiological outcomes will be recorded.

Intervention group (individualized dosing based on therapeutic monitoring)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years.
• Diagnosis of sepsis according to Sepsis-3 (SOFA ≥2).
• Initiation of treatment with beta-lactam antibiotics.
• Informed consent signed by the patient or their legal representative within the first 48 hours after the start of antibiotic therapy.

You may not qualify if:

• Pregnancy or breastfeeding.
• Known hypersensitivity to beta-lactams.
• Discontinuation of antibiotic treatment before the first TDM determination.
• Simultaneous participation in another clinical trial.

Sponsors & Collaborators

• Complexo Hospitalario Universitario de A Coruña: lead
• Hospital Clínico Universitario de Santiago de Compostela: collaborator

Study Sites (1)

Clinical Hospital of Santiago de Compostela

Santiago de Compostela, A Coruña, 15705, Spain

Location

Related Publications (7)

• Suarez D, Ferrer R, Artigas A, Azkarate I, Garnacho-Montero J, Goma G, Levy MM, Ruiz JC; Edusepsis Study Group. Cost-effectiveness of the Surviving Sepsis Campaign protocol for severe sepsis: a prospective nation-wide study in Spain. Intensive Care Med. 2011 Mar;37(3):444-52. doi: 10.1007/s00134-010-2102-3. Epub 2010 Dec 9.

  PMID: 21152895 BACKGROUND

• Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. No abstract available.

  PMID: 23984731 BACKGROUND

• Sakr Y, Jaschinski U, Wittebole X, Szakmany T, Lipman J, Namendys-Silva SA, Martin-Loeches I, Leone M, Lupu MN, Vincent JL; ICON Investigators. Sepsis in Intensive Care Unit Patients: Worldwide Data From the Intensive Care over Nations Audit. Open Forum Infect Dis. 2018 Nov 19;5(12):ofy313. doi: 10.1093/ofid/ofy313. eCollection 2018 Dec.

  PMID: 30555852 BACKGROUND

• Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, Fleischmann-Struzek C, Machado FR, Reinhart KK, Rowan K, Seymour CW, Watson RS, West TE, Marinho F, Hay SI, Lozano R, Lopez AD, Angus DC, Murray CJL, Naghavi M. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020 Jan 18;395(10219):200-211. doi: 10.1016/S0140-6736(19)32989-7.

  PMID: 31954465 BACKGROUND

• Perner A, Gordon AC, De Backer D, Dimopoulos G, Russell JA, Lipman J, Jensen JU, Myburgh J, Singer M, Bellomo R, Walsh T. Sepsis: frontiers in diagnosis, resuscitation and antibiotic therapy. Intensive Care Med. 2016 Dec;42(12):1958-1969. doi: 10.1007/s00134-016-4577-z. Epub 2016 Oct 1.

  PMID: 27695884 BACKGROUND

• Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing Sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med. 2017 Aug 3;377(5):414-417. doi: 10.1056/NEJMp1707170. Epub 2017 Jun 28. No abstract available.

  PMID: 28658587 BACKGROUND

• Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.

  PMID: 26903338 BACKGROUND

MeSH Terms

Conditions

Sepsis

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Iria Varela Rey, Pharmacist

CONTACT

+34697538722; iriavarela13@gmail.com

Manuel A Gómez-Rios, Anesthesiologist

CONTACT

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The randomization sequence will be generated using independent software (randomization.com). Concealment will be ensured using opaque, sequentially numbered envelopes and an electronic case report form (eCRF) that is locked until assignment. Outcome assessors will remain blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Anesthesiologist

Model Details: OPTIBETA is a pragmatic, randomized, controlled, low-intervention, hospital-based clinical trial. Patients will be randomly assigned in a 1:1 ratio to one of the following groups: * Intervention: individualized dosing of beta-lactam antibiotics guided by therapeutic drug monitoring (TDM) with adjustment according to pharmacokinetic/pharmacodynamic (PK/PD) targets. * Control: standard dosing based on clinical guidelines, without individualized adjustment. The study will be open-label, although the evaluators of clinical and microbiological outcomes will be blinded to treatment assignment in order to reduce observation bias.

Study Record Dates

• First Submitted: November 14, 2025
• First Posted: December 8, 2025
• Study Start: January 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): January 1, 2029
• Last Updated: December 8, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)