RESUMEN
Concentration-therapeutic efficacy relationships have been observed for several therapeutic monoclonal antibodies (TmAb), where low circulating levels can result in ineffective treatment and high concentrations can cause adverse reactions. Rapid therapeutic drug monitoring (TDM) of TmAb drugs would provide the opportunity to adjust an individual patient's dosing regimen to improve treatment results. However, TDM for immunotherapies is currently limited to centralised testing methods with long sample-collection to result timeframes. Here, we show four point-of-care (PoC) TmAb biosensors by combining anti-idiotypic Affimer proteins and NanoBiT split luciferase technology at a molecular level to provide a platform for rapid quantification (<10 minutes) for four clinically relevant TmAb (rituximab, adalimumab, ipilimumab and trastuzumab). The rituximab sensor performed best with 4 pM limit of detection (LoD) and a quantifiable range between 8 pM-2 nM with neglectable matrix effects in serum up to 1%. After dilution of serum samples, the resulting quantifiable range for all four sensors falls within the clinically relevant range and compares favourably with the sensitivity and/or time-to-result of current ELISA standards. Further development of these sensors into a PoC test may improve treatment outcome and quality of life for patients receiving immunotherapy.
RESUMEN
Rapid detection of protein and small-molecule analytes is a valuable technique across multiple disciplines, but most in vitro testing of biological or environmental samples requires long, laborious processes and trained personnel in laboratory settings, leading to long wait times for results and high expenses. Fusion of recognition with reporter elements has been introduced to detection methods such as enzyme-linked immunoassays (ELISA), with enzyme-conjugated secondary antibodies removing one of the many incubation and wash steps. Chimeric protein switch biosensors go further and provide a platform for homogenous mix-and-read assays where long wash and incubation steps are eradicated from the process. Chimeric protein switch biosensors consist of an enzyme switch (the reporter) coupled to a recognition element, where binding of the analyte results in switching the activity of the reporter enzyme on or off. Several chimeric protein switch biosensors have successfully been developed for analytes ranging from small molecule drugs to large protein biomarkers. There are two main formats of chimeric protein switch biosensor developed, one-component and multi-component, and these formats exhibit unique advantages and disadvantages. Genetically fusing a recognition protein to the enzyme switch has many advantages in the production and performance of the biosensor. A range of immune and synthetic binding proteins have been developed as alternatives to antibodies, including antibody mimetics or antibody fragments. These are mainly small, easily manipulated proteins and can be genetically fused to a reporter for recombinant expression or manipulated to allow chemical fusion. Here, aspects of chimeric protein switch biosensors will be reviewed with a comparison of different classes of recognition elements and switching mechanisms.
RESUMEN
Elastomeric infusion pumps (EMPs) have been implemented in many fields, including analgesia, chemotherapy and cardiology. Their application in antimicrobials is mainly limited to the outpatient setting, but with a need to optimise inpatient antimicrobial treatment, the use of EMPs presents a potential option. This review aimed to identify if the use of EMPs within an inpatient setting is feasible, effective and safe for antimicrobial use. Criteria for inclusion were human studies that involved the treatment of an infection with intravenous antimicrobial agents via an EMP. A search strategy was developed covering both the indexed and grey literature, with all study designs included. The review found 1 eligible study enrolling 6 patients. There was strong patient preference for EMPs (6/6), and daily tasks were easily completed whilst attached to the EMP. Nurses (5/5) also preffered the pumps, and the majority reported them as easy to use. The review has identified the need for further research in the area. Evidence for the use of EMPs to administer antibiotics in the inpatient setting is scarce, and more work is needed to understand the advantages to patients, to healthcare workers and from an antimicrobial stewardship perspective. Potential disadvantages that may put patients at risk also need investigating.
RESUMEN
Adjusting dosing regimens based on measurements of carbapenem levels may improve carbapenem exposure in patients. This systematic review aims to describe the effect carbapenem therapeutic drug monitoring (TDM) has on health outcomes, including the emergence of antimicrobial resistance (AMR). Four databases were searched for studies that reported health outcomes following adjustment to dosing regimens, according to measurements of carbapenem concentration. Bias in the studies was assessed with risk of bias analysis tools. Study characteristics and outcomes were tabulated and a narrative synthesis was performed. In total, 2 randomised controlled trials (RCTs), 17 non-randomised studies, and 19 clinical case studies were included. Significant variation in TDM practice was seen; consequently, a meta-analysis was unsuitable. Few studies assessed impacts on AMR. No significant improvement on health outcomes and no detrimental effects of carbapenem TDM were observed. Five cohort studies showed significant associations between achieving target concentrations and clinical success, including suppression of resistance. Studies in this review showed no obvious improvement in clinical outcomes when TDM is implemented. Optimisation and standardisation of carbapenem TDM practice are needed to improve intervention success and enable study synthesis. Further suitably powered studies of standardised TDM are required to assess the impact of TMD on clinical outcomes and AMR.
RESUMEN
BACKGROUND: Dosing regimens guided by therapeutic drug monitoring (TDM) may be able to improve penicillin exposure in patients, which could result in improved patient health outcomes. OBJECTIVES: This systematic review aims to describe the impact penicillin TDM has on health outcomes, including antimicrobial resistance (AMR). METHODS: Studies measuring penicillins in patient samples that adjusted regimens according to the result, and reported health outcomes were selected. Study bias was assessed according to study type. Included study characteristics were tabulated and described by narrative synthesis. RESULTS: Three randomized controlled trials (RCTs), 16 cohort studies, and 9 case studies were included. No RCTs showed statistically significant improvements in health outcomes. Five cohort studies showed improvement in at least one health outcome associated with target attainment. However, there was a high risk of bias in all studies for health outcomes. One study assessed the impact of penicillin TDM on AMR and found that improved target attainment was associated with suppression of resistance. No studies found a detrimental effect of penicillin TDM. CONCLUSIONS: There is little evidence to suggest that TDM improves health outcomes, however neither health outcomes nor impact on AMR were adequately addressed. Variations in TDM implementation meant that a meta-analysis was not suitable. Penicillin TDM needs standardization, however there is currently no clear evidence of optimal conditions. Suitably powered studies are required to resolve the ambiguity surrounding the impact of TDM on clinical outcomes, including AMR. Further, standardized protocols and concentration targets need to be identified for TDM to be implemented successfully.
