Infectious Disease · Medical Literature
Therapeutic monitoring of beta-lactams in critically ill patients with sepsis: Clinical trial protocol.
Abstract
Sepsis is a leading cause of morbidity and mortality among hospitalized 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 optimise dosing, but its routine clinical implementation remains limited. To evaluate whether individualized β-lactam dosing guided by TDM reduces time to full clinical recovery compared with standard dosing in hospitalized patients with sepsis (ICU and ward). OPTIBETA is a pragmatic, randomized, controlled, open-label clinical trial with blinded outcome assessment 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. We hypothesize that TDM-guided dosing will reduce time to clinical cure, improve overall outcomes, and decrease adverse events compared with standard dosing. OPTIBETA will provide high-quality evidence on the role of β-lactam TDM in hospitalized patients with sepsis and may support its inclusion in antimicrobial stewardship programs.
Clinical relevance
In hospitalized adult patients with sepsis (ICU and infectious diseases ward), does individualized β-lactam dosing guided by therapeutic drug monitoring (TDM) reduce time to complete clinical recovery compared with standard weight-based/fixed dosing? __SNAPSHOT__ {"studyDesign":"Pragmatic, randomized, controlled, open-label clinical trial with blinded outcome assessment (PROBE design) — protocol publication only; no efficacy results reported","setting":"Single tertiary-care hospital in Spain (ICU and infectious diseases ward)","sampleSize":"Not reported in the published protocol abstract; sample size calculation details not available from abstract alone","population":"Adults (≥18 years) admitted to the ICU or infectious diseases ward with a diagnosis of sepsis, receiving β-lactam antibiotics","intervention":"Individualized β-lactam dosing guided by TDM with dose adjustments targeted to pharmacokinetic/pharmacodynamic (PK/PD) goals","comparator":"Standard β-lactam dosing (non-TDM-guided, conventional empirical or protocol-driven dosing)","primaryOutcome":"Time to complete clinical cure","followUp":"Not reported in the abstract","fundingSource":"Not reported"}
Key findings
This is a trial protocol publication (PMID 42309277); no efficacy, safety, or pharmacological outcome data are reported. The abstract describes study rationale, design, and intended endpoints only. The OPTIBETA trial hypothesizes that TDM-guided dosing will reduce time to clinical cure, improve overall outcomes, and decrease adverse events compared with standard dosing, but all such findings remain speculative pending trial completion. Secondary outcomes are stated to include survival, microbiological cure, hospital length of stay, and adverse drug events, but no results, effect sizes, p-values, confidence intervals, or NNT/NNH values are available. This summary is based solely on the published protocol abstract.
Practice implications
This publication establishes the rationale and methodology for the OPTIBETA trial; it does not establish efficacy or harm. The study addresses a genuine evidence gap: β-lactams exhibit time-dependent pharmacodynamics, and high pharmacokinetic variability in critically ill sepsis patients makes achievement of therapeutic concentrations with standard dosing unreliable. Existing meta-analytic data suggest TDM-guided dosing is associated with improved clinical and microbiological cure rates but not with reduced mortality or shortened length of stay, and two large prior RCTs in critically ill patients have not demonstrated net clinical benefit of TDM. The OPTIBETA trial is notable for including both ICU and general infectious diseases ward patients — a broader population than most prior trials — and for using time to clinical cure (a patient-centered endpoint) as the primary outcome rather than a surrogate. Results cannot yet be applied to clinical practice. Patients inadequately represented include those with immunocompromise, renal replacement therapy, and augmented renal clearance, whose representation in the OPTIBETA cohort is unknown. Because only an abstract of the protocol is available, full methodological details (sample size, power assumptions, stopping rules, specific PK/PD targets, beta-lactam agents included, blinding procedures) could not be verified. __LIMITATIONS__ This is a protocol publication only — no outcome data are available for appraisal; clinical conclusions cannot be drawn from this paper alone.,Single-center design at one tertiary hospital in Spain limits generalizability to other healthcare systems, resource settings, and patient populations.,Open-label allocation (PROBE design) introduces potential for performance bias in dosing decisions and clinical management, despite blinded outcome assessment.,Sample size, power calculations, and specific PK/PD targets used to guide TDM arm dosing adjustments are not reported in the available abstract.,Randomization 1:1 across two distinct clinical environments (ICU and infectious diseases ward) with substantially different patient acuity and pharmacokinetic profiles may introduce heterogeneity in the primary endpoint without pre-specified subgroup analyses.,The primary endpoint (time to complete clinical cure) requires rigorous, standardized clinical definitions to minimize subjective ascertainment bias even with blinded assessors.,Prior RCTs (e.g., the piperacillin/tazobactam TDM trial, the DOLPHIN trial) failed to demonstrate benefit of TDM on SOFA score or mortality in similar critically ill populations, raising questions about whether a single-center trial is adequately powered to detect a clinically meaningful difference on a time-to-event endpoint.,Funding source is not reported, making assessment of potential conflict-of-interest or industry influence impossible at this stage.,Generalizability to healthcare settings without robust real-time drug assay infrastructure or clinical pharmacokinetics support services is unclear. __BOTTOM_LINE_CATEGORY__ not_ready_for_clinical_application __BOTTOM_LINE__ OPTIBETA is a well-conceived pragmatic RCT protocol designed to evaluate whether TDM-guided β-lactam dosing reduces time to clinical cure in hospitalized sepsis patients across both ICU and ward settings. No efficacy data are yet available, and existing RCT evidence has not demonstrated a mortality benefit from β-lactam TDM in critically ill patients. Clinicians should not alter current β-lactam dosing practices based on this protocol publication; results of the completed trial will be required before any practice change can be considered.