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      Towards precision medicine: Therapeutic drug monitoring–guided dosing of vancomycin and β-lactam antibiotics to maximize effectiveness and minimize toxicity

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          Abstract

          Purpose

          The goal of this review is to explore the role of antimicrobial therapeutic drug monitoring (TDM), especially in critically ill, obese, and older adults, with a specific focus on β-lactams and vancomycin.

          Summary

          The continued rise of antimicrobial resistance prompts the need to optimize antimicrobial dosing. The aim of TDM is to individualize antimicrobial dosing to achieve antibiotic exposures associated with improved patient outcomes. Initially, TDM was developed to minimize adverse effects during use of narrow therapeutic index agents. Today, patient and organism complexity are expanding the need for precision dosing through TDM services. Alterations of pharmacokinetics and pharmacodynamics (PK/PD) in the critically ill, obese, and older adult populations, in conjunction with declining organism susceptibility, complicate attainment of therapeutic targets. Over the last decade, antimicrobial TDM has expanded with the emergence of literature supporting β-lactam TDM and a shift from monitoring vancomycin trough concentrations to monitoring of the ratio of area under the concentration (AUC) curve to minimum inhibitory concentration (MIC). PK/PD experts should be at the forefront of implementing precision dosing practices.

          Conclusion

          Precision dosing through TDM is expanding and is especially important in populations with altered PK/PD, including critically ill, obese, and older adults. Due to wide PK/PD variability in these populations, TDM is vital to maximize antimicrobial effectiveness and decrease adverse event rates. However, there is still a need for studies connecting TDM to patient outcomes. Providing patient-specific care through β-lactam TDM and transitioning to vancomycin AUC/MIC monitoring may be challenging, but with experts at the forefront of this initiative, PK-based optimization of antimicrobial therapy can be achieved.

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          Most cited references60

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          DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?

          Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.
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            Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.

            The objective of this study was to evaluate the relationship of the predicted pharmacodynamic parameters 24-h area under the inhibitory curve (AUIC=area under the concentration-time curve for 24h of dosing/minimum inhibitory concentration (AUC0-24/MIC) and time above the minimum inhibitory concentration (T>MIC) with clinical and microbiological outcomes in patients with bacteraemia and sepsis treated with cefepime or ceftazidime. Pharmacokinetic and pharmacodynamic parameters were derived for 76 of 107 patients enrolled in two prospective, randomised, clinical trials comparing cefepime with ceftazidime for the treatment of sepsis with bacteraemia, lower respiratory tract infection or complicated urinary tract infection. The relationships between the pharmacodynamic parameters and outcomes were examined. Whilst no significant differences in clinical outcomes were observed between cefepime and ceftazidime, there were significant differences in the pharmacodynamic analysis. Patients with an AUIC> or =250 had significantly greater clinical cure (79% vs. 33%; P=0.002) and bacteriological eradication (96% vs. 44%; P MIC of 100% had significantly greater clinical cure (82% vs. 33%; P=0.002) and bacteriological eradication (97% vs. 44%; P MIC of MIC was <100%.
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              Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations.

              β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets. Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR). Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis. Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.
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                Author and article information

                Journal
                American Journal of Health-System Pharmacy
                Oxford University Press (OUP)
                1079-2082
                1535-2900
                June 15 2020
                June 15 2020
                Affiliations
                [1 ]Infectious Diseases Research Program, Veterans Affairs Medical Center, Providence, RI
                [2 ]Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI
                [3 ]Merck & Co., Inc., Kenilworth, NJ
                [4 ]Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
                [5 ]University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine & Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Brisbane, Australia
                [6 ]Royal Brisbane and Women’s Hospital, Brisbane, Australia
                Article
                10.1093/ajhp/zxaa128
                32537644
                0ce72ee6-33e4-4c8b-98e1-28f3ef26fdd8
                © 2020
                History

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