Study protocol for ADAPT-TDM: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring.

INTRODUCTION: Critically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity. Therapeutic drug monitoring (TDM) involves adjusting doses based on measured plasma concentrations and individualising dosing to improve the likelihood of improving exposure. Despite its potential benefits, its adoption has been slow, and data on implementation, dose adaptation and safety are sparse. The aim of this trial is to assess the feasibility and fidelity of implementing beta-lactam TDM-guided dosing in the intensive care unit setting. METHODS AND ANALYSIS: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring (ADAPT-TDM) is a single-centre, unblinded, feasibility randomised controlled trial aiming to enroll up to 60 critically ill adult participants (≥18 years). TDM and dose adjustment will be performed daily in the intervention group; the standard of care group will undergo plasma sampling, but no dose adjustment. The main outcomes include: (1) feasibility of recruitment, defined as the number of participants who are recruited from a pool of eligible participants, and (2) fidelity of TDM, defined as the degree to which TDM as a test is delivered as intended, from accurate sample collection, sample processing to result availability. Secondary outcomes include target attainment, uptake of TDM-guided dosing and incidence of neurotoxicity, hepatotoxicity and nephrotoxicity. ETHICS AND DISSEMINATION: This study has been approved by the Alfred Hospital human research ethics committee, Office of Ethics and Research Governance (reference: Project No. 565/22; date of approval: 22/11/2022). Prospective consent will be obtained and the study will be conducted in accordance with the Declaration of Helsinki. The finalised manuscript, including aggregate data, will be submitted for publication in a peer reviewed journal. ADAPT-TDM will determine whether beta-lactam TDM-guided dose adaptation is reproducible and feasible and provide important information required to implement this intervention in a phase III trial. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12623000032651.

Implementation Strategies Addressing Stakeholder-Perceived Barriers and Enablers to the Establishment of a Beta-Lactam Antibiotic Therapeutic Drug Monitoring Program: A Qualitative Analysis.

BACKGROUND: Therapeutic drug monitoring (TDM) of beta-lactam antibiotics (beta-lactams) is increasingly recommended for optimizing antibiotic exposure in intensive care patients with sepsis. However, limited data are available on the implementation of beta-lactam TDM in complex health care settings. Theory-based approaches were used to systematically explore barriers and enablers perceived by key stakeholders in the implementation of beta-lactam TDM in the intensive care unit. METHODS: In this qualitative descriptive study, the authors interviewed key stakeholders (n = 40): infectious disease physicians, intensive care unit physicians, pharmacists, clinical leaders, scientists, and nurses. The data were thematically analyzed and coded using the theoretical domains framework, and the codes and themes were mapped to the relevant domains of the capability, opportunity, and motivation behavior-change wheel model. RESULTS: Barriers included a lack of knowledge, experience, evidence, and confidence, which led to concerns about capability, lack of resources, and harm in straying from standard practice. Access to education and guidelines, on-site assays with short turnaround times, communication among teams, and workflow integration were identified as enablers. A focus on patient care, trust in colleagues, and endorsement by hospital leaders were strong motivators. Pharmacist and nursing stakeholder groups emerged as key targets in the implementation of strategies. CONCLUSIONS: Using theory-based approaches, the authors identified the key barriers and enablers to establishing beta-lactam TDM. These data were used to identify strategies, policies, and key target groups for the implementation of interventions.

The clinical application of beta-lactam antibiotic therapeutic drug monitoring in the critical care setting.

Critically ill patients have increased variability in beta-lactam antibiotic (beta-lactam) exposure due to alterations in their volume of distribution and elimination. Therapeutic drug monitoring (TDM) of beta-lactams, as a dose optimization and individualization tool, has been recommended to overcome this variability in exposure. Despite its potential benefit, only a few centres worldwide perform beta-lactam TDM. An important reason for the low uptake is that the evidence for clinical benefits of beta-lactam TDM is not well established. TDM also requires the availability of specific infrastructure, knowledge and expertise. Observational studies and systematic reviews have demonstrated that TDM leads to an improvement in achieving target concentrations, a reduction in potentially toxic concentrations and improvement of clinical and microbiological outcomes. However, a small number of randomized controlled trials have not shown a mortality benefit. Opportunities for improved study design are apparent, as existing studies are limited by their inclusion of heterogeneous patient populations, including patients that may not even have infection, small sample size, variability in the types of beta-lactams included, infections caused by highly susceptible bacteria, and varied sampling, analytical and dosing algorithm methods. Here we review the fundamentals of beta-lactam TDM in critically ill patients, the existing clinical evidence and the practical aspects involved in beta-lactam TDM implementation.

Immunogenicity, effectiveness, and safety of SARS-CoV-2 vaccination in people with HIV.

OBJECTIVES: People with HIV (PWH) experience a greater risk of morbidity and mortality following COVID-19 infection, and poorer immunological responses to several vaccines. We explored existing evidence regarding the immunogenicity, effectiveness, and safety of SARS-CoV-2 vaccines in PWH compared with controls. METHODS: We conducted a systematic search of electronic databases from January 2020 until June 2022, in addition to conference databases, to identify studies comparing clinical, immunogenicity, and safety in PWH and controls. We compared results between those with low (<350 cells/µl) and high (>350 cells/µl) CD4 + T-cell counts where possible. We performed a meta-analysis of seroconversion and neutralization responses to calculate a pooled risk ratio as the measure of effect. RESULTS: We identified 30 studies, including four reporting clinical effectiveness, 27 immunogenicity, and 12 reporting safety outcomes. PWH were 3% [risk ratio 0.97, 95% confidence interval (95% CI) 0.95-0.99] less likely to seroconvert and 5% less likely to demonstrate neutralization responses (risk ratio 0.95, 95% CI 0.91-0.99) following a primary vaccine schedule. Having a CD4 + T-cell count less than 350 cells/µl (risk ratio 0.91, 95% CI 0.83-0.99) compared with a CD4 + T-cell count more than 350 cells/µl, and receipt of a non-mRNA vaccine in PWH compared with controls (risk ratio 0.86, 95% CI 0.77-0.96) were associated with reduced seroconversion. Two studies reported worse clinical outcomes in PWH. CONCLUSION: Although vaccines appear well tolerated in PWH, this group experience poorer immunological responses following vaccination than controls, particularly with non-mRNA vaccines and low CD4 + T-cell counts. PWH should be prioritized for mRNA COVID-19 vaccines, especially PWH with more advanced immunodeficiency.

Beta-Lactam Antibiotic Therapeutic Drug Monitoring in Critically Ill Patients: A Systematic Review and Meta-Analysis.

Therapeutic drug monitoring (TDM) of beta-lactam antibiotics is recommended to address the variability in exposure observed in critical illness. However, the impact of TDM-guided dosing on clinical outcomes remains unknown. We conducted a systematic review and meta-analysis on TDM-guided dosing and clinical outcomes (all-cause mortality, clinical cure, microbiological cure, treatment failure, hospital and intensive care unit length of stay, target attainment, antibiotic-related adverse events, and emergence of resistance) in critically ill patients with suspected or proven sepsis. Eleven studies (n = 1463 participants) were included. TDM-guided dosing was associated with improved clinical cure (relative risk, 1.17; 95% confidence interval [CI], 1.04 to 1.31), microbiological cure (RR, 1.14; 95% CI, 1.03 to 1.27), treatment failure (RR, 0.79; 95% CI, .66 to .94), and target attainment (RR, 1.85; 95% CI, 1.08 to 3.16). No associations with mortality and length of stay were found. TDM-guided dosing improved clinical and microbiological cure and treatment response. Larger, prospective, randomized trials are required to better assess the utility of beta-lactam TDM in critically ill patients.

Old but not forgotten: Antibiotic allergies in General Medicine (the AGM Study).

OBJECTIVES: To determine the nature, prevalence and description accuracy of recorded antibiotic allergy labels (AALs) in a cohort of general medical inpatients, and to assess the feasibility of an oral antibiotic re-challenge study. DESIGN: Multicentre cross-sectional study. SETTING AND PARTICIPANTS: All patients admitted to the general medical units of Austin Health and Alfred Health, 18 May - 5 June 2015. MAIN OUTCOME MEASURES: Baseline demographics, medical and allergy history, infection diagnoses and antibiotic prescribing data for general medical inpatients were collected. A questionnaire was administered to clarify AAL history, followed by correlation of responses with electronic and admissions record descriptions. A hypothetical oral re-challenge in a supervised setting was offered to patients with low risk allergy phenotypes (non-immediate reaction, non-severe cutaneous adverse reaction, or unknown reaction more than 10 years ago). RESULTS: Of the 453 inpatients, 107 (24%) had an AAL (median age, 82 years; interquartile range, 74-87 years); 160 individual AALs were recorded, and there was a mismatch in AAL description between recording platforms in 25% of cases. Most patients with an AAL were women (64%; P < 0.001), and more presented with concurrent immunosuppression than those without an AAL (23% v 8%; P < 0.001). ß-Lactam penicillins were employed less frequently in patients with an AAL (16% v 35%; P = 0.02), while ceftriaxone (32% v 20%; P = 0.02) and fluoroquinolones (6% v 2%; P = 0.04) were used more often. Fifty-four per cent of patients with AALs were willing to undergo oral re-challenge, of whom 48% had a low risk allergy phenotype. CONCLUSIONS: AAL prevalence in general medical inpatients was 24%, and was associated with excessive use of broad spectrum antibiotics. Allergies in a large proportion of patients with AALs were incorrectly documented, and were non-immune-mediated and potentially amenable to oral re-challenge. A direct oral re-challenge study in carefully selected patients with low risk allergy phenotypes appears feasible.