Purpose
This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the ...intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.
Methods
Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes.
Results
TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients.
Conclusion
Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide.
Dried blood spot (DBS) analysis has been introduced more and more into clinical practice to facilitate Therapeutic Drug Monitoring (TDM). To assure the quality of bioanalytical methods, the design, ...development and validation needs to fit the intended use. Current validation requirements, described in guidelines for traditional matrices (blood, plasma, serum), do not cover all necessary aspects of method development, analytical- and clinical validation of DBS assays for TDM. Therefore, this guideline provides parameters required for the validation of quantitative determination of small molecule drugs in DBS using chromatographic methods, and to provide advice on how these can be assessed. In addition, guidance is given on the application of validated methods in a routine context. First, considerations for the method development stage are described covering sample collection procedure, type of filter paper and punch size, sample volume, drying and storage, internal standard incorporation, type of blood used, sample preparation and prevalidation. Second, common parameters regarding analytical validation are described in context of DBS analysis with the addition of DBS-specific parameters, such as volume-, volcano- and hematocrit effects. Third, clinical validation studies are described, including number of clinical samples and patients, comparison of DBS with venous blood, statistical methods and interpretation, spot quality, sampling procedure, duplicates, outliers, automated analysis methods and quality control programs. Lastly, cross-validation is discussed, covering changes made to existing sampling- and analysis methods. This guideline of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology on the development, validation and evaluation of DBS-based methods for the purpose of TDM aims to contribute to high-quality micro sampling methods used in clinical practice.
Bedaquiline, a new antituberculosis drug, has already been used in >50 countries. The emergence of bedaquiline resistance is alarming, as it may result in the rapid loss of this new drug. This ...article aims to review currently identified mechanisms of resistance and the emergence of bedaquiline resistance, and discuss strategies to delay the resistance acquisition. In vitro and clinical studies as well as reports from compassionate use have identified the threat of bedaquiline resistance and cross-resistance with clofazimine, emphasizing the crucial need for the systematic surveillance of resistance. Currently known mechanisms of resistance include mutations within the atpE, Rv0678, and pepQ genes. The development of standardized drug susceptibility testing (DST) for bedaquiline is urgently needed. Understanding any target and non-target-based mechanisms is essential to minimize resistance development and treatment failure and help to develop appropriate DST for bedaquiline and genetic-based resistance screening.
Abstract
Delamanid, a-first-in-class bicyclic nitroimidazole, was recently approved for multidrug-resistant tuberculosis treatment. Pitted against the hope for improving treatment outcomes is the ...threat of the rapid resistance emergence. This review provides information on the mechanisms of action, resistance emergence, and drug susceptibility testing (DST) for delamanid. Delamanid resistance has already been reported in both in vitro experiments and clinical settings. Although mutations conferring delamanid resistance have been identified in fbiA, fbiB, fbiC, ddn, and fgd1 genes of Mycobacterium tuberculosis, knowledge about the molecular resistance mechanisms is limited, and there remains no standardized DST method. The rapid acquisition of delamanid resistance emphasizes the need for optimal use of new drugs, the need for drug resistance surveillance, and a comprehensive understanding of drug resistance mechanisms. Further studies are necessary to investigate genetic and phenotypic changes that determine clinically relevant delamanid resistance to help develop a rapid delamanid DST.
Although delamanid resistance has been reported in both in vitro and clinical Mycobacterium tuberculosis isolates and mutations conferring delamanid resistance have been identified in fbiA, fbiB, fbiC, ddn, and fgd, there remains no standardized drug susceptibility testing method, and knowledge about clinically relevant molecular resistance mechanisms is limited.
Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients ...with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure‐response relationship with either a narrow therapeutic window, large dose‐exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non‐compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM‐guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided.
We developed a method for the analysis of four immunosuppressants in dried blood spot (DBS) samples to facilitate therapeutic drug monitoring for transplant patients outside the hospital. An 8mm disc ...from the central part of the DBS was punched, extracted and followed by LC-MS/MS analysis. The method was validated with ranges from 1.00–50.0µg/L for tacrolimus, sirolimus and everolimus, and from 20.0–2000µg/L for cyclosporin A. The validation showed a maximum overall bias of 13.0% for the sirolimus LLOQ, while the maximum overall CV was 15.7% for the everolimus LLOQ. All four immunosuppressants showed to be stable in DBS for at least 7 days at 22°C. The volume of the blood spot showed to have minor effect on measured concentrations. A cross-validation test between the 31 ET CHR paper and the Whatman FTA DMPK-C cards showed no significant difference between the two types of paper. During validation the hematocrit (HT) showed to have significant influence on the analytical results. When the measured concentrations were corrected for the effect of the HT, biases improved significantly. Additional recovery tests proved that the combination of especially low HT and high concentration does not only affect the spot size but can also affect the extraction recoveries of sirolimus and especially everolimus. Although the tested parameters like HT and concentrations are extreme and unlikely for routine analysis of outpatients, the fundamental effect of the combination of these parameters on extraction recoveries are proven with this research. The protein binding in the blood and hydrogen binding to the cellulose of the paper is suggested to influence extractions and gives new insights in the extraction methodology of DBS samples.
The observed HT effect during the validation appeared to be negligible during the correlation study as no concentration corrections for the HT values were needed. Nevertheless, results from DBS samples with extremely high concentrations combined with extremely low HT values should be interpreted with caution. The patient correlation study showed good correlations with R2 values higher than 0.87 between venous whole blood and venous DBS samples were observed for all four immunosuppressants. The Passing & Bablok plots showed positive biases of the slopes of 18% for tacrolimus and less than 12% for sirolimus, everolimus and cyclosporin A. The validated method, proved stability of the immunosuppressants in DBS, and the correlation study showed the capability of the DBS method to be used as an alternative for whole blood analysis in therapeutic drug monitoring.
•Fast dried blood spot analysis without extensive sample preparation.•Cross-validation test performed for 31 ET CHR paper and Whatman FTA DMPK-C cards.•The performed correlation study showed good correlations.•Immunosuppressant extraction was affected by extreme concentration and hematocrit.•Substance protein binding and cellulose binding affinity may affect recovery.
Abstract
A World Health Organization workshop systematically examined the evidence base for dosing second-line tuberculosis drugs, identifying knowledge gaps. To fill these in, ...pharmacokinetics/pharmacodynamics, Monte Carlo experiments, and artificial intelligence algorithms were used in hollow-fiber model studies and clinical data analyses.
During an infection or inflammation, several drug-metabolizing enzymes in the liver are down-regulated, including cytochrome P450 iso-enzymes. Since voriconazole is extensively metabolized by ...cytochrome P450 iso-enzymes, the metabolism of voriconazole can be influenced during inflammation via reduced clearance of the drug, resulting in higher voriconazole trough concentrations.
To investigate prospectively the influence of inflammation on voriconazole metabolism and voriconazole trough concentrations.
A prospective observational study was performed at the University Medical Center Groningen. Patients were eligible for inclusion if they were ≥18 years old and treated with voriconazole. Voriconazole and voriconazole-N-oxide concentrations were determined in discarded blood samples. To determine the degree of inflammation, C-reactive protein (CRP) concentrations were used. Subsequently, a longitudinal data analysis was performed to assess the effect of inflammation on the metabolic ratio and voriconazole trough concentration.
Thirty-four patients were included. In total 489 voriconazole trough concentrations were included in the longitudinal data analysis. This analysis showed that inflammation, reflected by CRP concentrations, significantly influenced the metabolic ratio, voriconazole trough concentration and voriconazole-N-oxide concentration (all P < 0.001), when corrected for other factors that could influence voriconazole metabolism. The metabolic ratio was decreased by 0.99229
and the voriconazole-N-oxide concentration by 0.99775
, while the voriconazole trough concentration was increased by 1.005321
, where N is the difference in CRP units (in mg/L).
This study shows that voriconazole metabolism is decreased during inflammation, resulting in higher voriconazole trough concentrations. Therefore, frequent monitoring of voriconazole serum concentrations is recommended during and following severe inflammation.
Respiratory tract infection with pneumoviruses (PVs) and paramyxoviruses (PMVs) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). ...Ribavirin may be a treatment option but its effectiveness is unclear, especially with respect to infection severity. We retrospectively analyzed 10 years of PV/PMV infections in LTRs. The main end points were forced expiratory volume in 1 second (FEV1) at 3 and 6 months postinfection, expressed as a percentage of pre‐infection FEV1 and incidence of new or progressed CLAD 6 months postinfection. A total of 139 infections were included: 88 severe infections (63%) (defined as >10% FEV1 loss at infection) and 51 mild infections (37%) (≤10% FEV1 loss). Overall postinfection CLAD incidence was 20%. Associations were estimated on postinfection FEV1 for ribavirin vs no ribavirin (+13.2% 95% CI: 7.79; 18.67) and severe vs mild infection (−11.1% 95% CI: −14.76; −7.37). Factors associated with CLAD incidence at 6 months were ribavirin treatment (odds ratio (OR 95% CI) 0.24 0.10; 0.59), severe infection (OR 95% CI 4.63 1.66; 12.88), and mycophenolate mofetil use (OR 95% CI 0.38 0.14; 0.97). These data provide valuable information about the outcomes of lung transplant recipients with these infections and suggests possible associations of ribavirin use and infection severity with long‐term outcomes. Well‐designed prospective trials are needed to confirm these findings.
Respiratory syncytial virus, parainfluenza virus, and human metapneumovirus infections in lung transplant recipients are often accompanied by severe and acute decline in lung function and a future risk of postinfection chronic lung allograft dysfunction, which appears increased with severe infection but decreased with ribavirin treatment.
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