Cefadroxil and cephalexin pharmacokinetics and pharmacodynamics in children with musculoskeletal infections.

Cephalexin, a first-generation cephalosporin, is the first-line oral therapy for children with musculoskeletal infections due to methicillin-susceptible Staphylococcus aureus (MSSA). Cefadroxil, a similar first-generation cephalosporin, is an attractive alternative to cephalexin given its longer half-life. In this study, we describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of cephalexin and cefadroxil in children with musculoskeletal infections. Children aged 6 months to 18 years with a musculoskeletal infection were enrolled in a prospective, open-label, crossover PK study and given single oral doses of cefadroxil (50-75 mg/kg up to 2,000 mg) and cephalexin (50 mg/kg up to 1,375 mg). Population PK models were developed and used for dosing simulations. Our primary PD target was the achievement of free antibiotic concentrations above the minimum inhibitory concentration (fT >MIC) for 40% of the day for MICs ≤ 4 mg/L. PK of cephalexin (n = 15) and cefadroxil (n = 14) were best described using a one-compartment, first-order absorption model, with a lag time component for cefadroxil. PK parameters were notable for cefadroxil's longer half-life (1.61 h) than cephalexin's (1.10 h). For pediatric weight bands, our primary PD target was achieved by cephalexin 25 mg/kg/dose, maximum 750 mg/dose, administered three times daily and cefadroxil 40 mg/kg/dose, maximum 1,500 mg/dose, administered twice daily. More aggressive dosing was required to achieve higher PD targets. Among children with musculoskeletal infections, oral cephalexin and cefadroxil achieved PD targets for efficacy against MSSA. Given less frequent dosing, twice-daily cefadroxil should be further considered as an alternative to cephalexin for oral step-down therapy for serious infections due to MSSA.

Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review.

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.

Impact of Vancomycin Loading Doses and Dose Escalation on Glomerular Function and Kidney Injury Biomarkers in a Translational Rat Model.

Vancomycin-induced kidney injury is common, and outcomes in humans are well predicted by animal models. This study employed our translational rat model to investigate temporal changes in the glomerular filtration rate (GFR) and correlations with kidney injury biomarkers related to various vancomycin dosing strategies. First, Sprague-Dawley rats received allometrically scaled loading doses or standard doses. Rats that received a loading dose had low GFRs and increased urinary injury biomarkers (kidney injury molecule 1 [KIM-1] and clusterin) that persisted through day 2 compared to those that did not receive a loading dose. Second, we compared low and high allometrically scaled vancomycin doses to a positive acute kidney injury control of high-dose folic acid. Rats in both the low- and high-dose vancomycin groups had higher GFRs on all dosing days than the positive-control group. When the two vancomycin groups were compared, rats that received the low dose had significantly higher GFRs on days 1, 2, and 4. Compared to low-dose vancomycin, the KIM-1 was elevated among rats in the high-dose group on dosing day 3. The GFR correlated most closely with the urinary injury biomarker KIM-1 on all experimental days. Vancomycin loading doses were associated with significant losses of kidney function and elevations of urinary injury biomarkers. In our translational rat model, both the degree of kidney function decline and urinary biomarker increases corresponded to the magnitude of the vancomycin dose (i.e., a higher dose resulted in worse outcomes).

Iohexol-Measured Glomerular Filtration Rate and Urinary Biomarker Changes between Vancomycin and Vancomycin Plus Piperacillin-Tazobactam in a Translational Rat Model.

Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination. Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 h. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated with the urinary biomarkers kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to the control, rats that received vancomycin had numerically lower GFRs after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin plus piperacillin-tazobactam (vancomycin+piperacillin-tazobactam) did not exhibit worse kidney function or injury biomarkers than rats receiving vancomycin alone. The combination of vancomycin and piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.

Population pharmacokinetic model of cefepime for critically ill adults: a comparative assessment of eGFR equations.

Cefepime exhibits highly variable pharmacokinetics in critically ill patients. The purpose of this study was to develop and qualify a population pharmacokinetic model for use in the critically ill and investigate the impact of various estimated glomerular filtration rate (eGFR) equations using creatinine, cystatin C, or both on model parameters. This was a prospective study of critically ill adults hospitalized at an academic medical center treated with intravenous cefepime. Individuals with acute kidney injury or on kidney replacement therapy or extracorporeal membrane oxygenation were excluded. A nonlinear mixed-effects population pharmacokinetic model was developed using data collected from 2018 to 2022. The 120 included individuals contributed 379 serum samples for analysis. A two-compartment pharmacokinetic model with first-order elimination best described the data. The population mean parameters (standard error) in the final model were 7.84 (0.24) L/h for CL1 and 15.6 (1.45) L for V1. Q was fixed at 7.09 L/h and V2 was fixed at 10.6 L, due to low observed interindividual variation in these parameters. The final model included weight as a covariate for volume of distribution and the eGFRcr-cysC (mL/min) as a predictor of drug clearance. In summary, a population pharmacokinetic model for cefepime was created for critically ill adults. The study demonstrated the importance of cystatin C to prediction of cefepime clearance. Cefepime dosing models which use an eGFR equation inclusive of cystatin C are likely to exhibit improved accuracy and precision compared to dosing models which incorporate an eGFR equation with only creatinine.

Individual meropenem epithelial lining fluid and plasma PK/PD target attainment.

It is unclear whether plasma is a reliable surrogate for target attainment in the epithelial lining fluid (ELF). The objective of this study was to characterize meropenem target attainment in plasma and ELF using prospective samples. The first 24-hour T>MIC was evaluated vs 1xMIC and 4xMIC targets at the patient (i.e., fixed MIC of 2 mg/L) and population [i.e., cumulative fraction of response (CFR) according to EUCAST MIC distributions] levels for both plasma and ELF. Among 65 patients receiving ≥24 hours of treatment, 40% of patients failed to achieve >50% T>4xMIC in plasma and ELF, and 30% of patients who achieved >50% T>4xMIC in plasma had <50% T>4xMIC in ELF. At 1xMIC and 4xMIC targets, 3% and 25% of patients with >95% T>MIC in plasma had <50% T>MIC in ELF, respectively. Those with a CRCL >115 mL/min were less likely to achieve >50%T>4xMIC in ELF (P < 0.025). In the population, CFR for Escherichia coli at 1xMIC and 4xMIC was >97%. For Pseudomonas aeruginosa, CFR was ≥90% in plasma and ranged 80%-85% in ELF at 1xMIC when a loading dose was applied. CFR was reduced in plasma (range: 75%-81%) and ELF (range: 44%-60%) in the absence of a loading dose at 1xMIC. At 4xMIC, CFR for P. aeruginosa was 60%-86% with a loading dose and 18%-62% without a loading dose. We found that plasma overestimated ELF target attainment inup to 30% of meropenem-treated patients, CRCL >115 mL/min decreased target attainment in ELF, and loading doses increased CFR in the population.

Making the case for precision dosing: visualizing the variability of cefepime exposures in critically ill adults.

OBJECTIVE: To investigate and describe the variability in cefepime exposures among 'real-world', critically ill patients by using population pharmacokinetic modelling and simulations, and with translation of these findings to visualizations. METHODS: A cohort of adult medical ICU patients who received cefepime with therapeutic drug monitoring was studied. Two compartment models were developed to estimate cefepime clearance (Model 1) and simulate cefepime exposures among 1000 patients, each with identical creatinine clearance of 60 mL/min and receiving a regimen of cefepime 1 gram IV over 30 minutes, every 8 hours (Model 2). Variability in the relationship between cefepime clearance and creatinine clearance (CrCL) was visualized, and a random, representative sample of 10 simulated patients was utilized to illustrate variability in cefepime exposures. RESULTS: A total of 75 adult medical ICU patients (52% female) and 98 serum cefepime samples were included in the study. Population parameter estimates for cefepime displayed a wide range of variation in Model 1 (CV: 45% to 95%), with low bias at the individual level at 0.226 mg/L but high bias in the population model 10.6 mg/L. Model 2 displayed similar fits, demonstrating that correcting for individual patient creatinine clearance slightly improves the bias of the population model (bias = 4.31 mg/L). Among 10 simulated patients that a clinician would deem similar from a dosing perspective (i.e. equivalent creatinine clearance), maximum concentrations after three simulated doses varied more than 8-fold from 41.2 to 339 mg/L at the 5th and 95th percentiles, and clearance profiles were highly different. CONCLUSION: Creatinine clearance estimates alone are inadequate for predicting cefepime exposures. Wide variations in cefepime exposure exist among ICU patients, even for those with similar kidney function estimates. Current population adjustment schemes based solely on creatinine clearance will result in unintended high and low exposures leading to safety and efficacy concerns, respectively.

Why is the Implementation of Beta-Lactam Therapeutic Drug Monitoring for the Critically Ill Falling Short? A Multicenter Mixed-Methods Study.

BACKGROUND: Beta-lactam therapeutic drug monitoring (BL TDM; drug level testing) can facilitate improved outcomes in critically ill patients. However, only 10%-20% of hospitals have implemented BL TDM. This study aimed to characterize provider perceptions and key considerations for successfully implementing BL TDM. METHODS: This was a sequential mixed-methods study from 2020 to 2021 of diverse stakeholders at 3 academic medical centers with varying degrees of BL TDM implementation (not implemented, partially implemented, and fully implemented). Stakeholders were surveyed, and a proportion of participants completed semistructured interviews. Themes were identified, and findings were contextualized with implementation science frameworks. RESULTS: Most of the 138 survey respondents perceived that BL TDM was relevant to their practice and improved medication effectiveness and safety. Integrated with interview data from 30 individuals, 2 implementation themes were identified: individual internalization and organizational features. Individuals needed to internalize, make sense of, and agree to BL TDM implementation, which was positively influenced by repeated exposure to evidence and expertise. The process of internalization appeared more complex with BL TDM than with other antibiotics (ie, vancomycin). Organizational considerations relevant to BL TDM implementation (eg, infrastructure, personnel) were similar to those identified in other TDM settings. CONCLUSIONS: Broad enthusiasm for BL TDM among participants was found. Prior literature suggested that assay availability was the primary barrier to implementation; however, the data revealed many more individual and organizational attributes, which impacted the BL TDM implementation. Internalization should particularly be focused on to improve the adoption of this evidence-based practice.

International survey of antibiotic dosing and monitoring in adult intensive care units.

BACKGROUND: In recent years, numerous dosing studies have been conducted to optimize therapeutic antibiotic exposures in patients with serious infections. These studies have led to the inclusion of dose optimization recommendations in international clinical practice guidelines. The last international survey describing dosing, administration and monitoring of commonly prescribed antibiotics for critically ill patients was published in 2015 (ADMIN-ICU 2015). This study aimed to describe the evolution of practice since this time. METHODS: A cross-sectional international survey distributed through professional societies and networks was used to obtain information on practices used in the dosing, administration and monitoring of vancomycin, piperacillin/tazobactam, meropenem and aminoglycosides. RESULTS: A total of 538 respondents (71% physicians and 29% pharmacists) from 409 hospitals in 45 countries completed the survey. Vancomycin was mostly administered as an intermittent infusion, and loading doses were used by 74% of respondents with 25 mg/kg and 20 mg/kg the most favoured doses for intermittent and continuous infusions, respectively. Piperacillin/tazobactam and meropenem were most frequently administered as an extended infusion (42% and 51%, respectively). Therapeutic drug monitoring was undertaken by 90%, 82%, 43%, and 39% of respondents for vancomycin, aminoglycosides, piperacillin/tazobactam, and meropenem, respectively, and was more frequently performed in high-income countries. Respondents rarely used dosing software to guide therapy in clinical practice and was most frequently used with vancomycin (11%). CONCLUSIONS: We observed numerous changes in practice since the ADMIN-ICU 2015 survey was conducted. Beta-lactams are more commonly administered as extended infusions, and therapeutic drug monitoring use has increased, which align with emerging evidence.

Glomerular Function and Urinary Biomarker Changes between Vancomycin and Vancomycin plus Piperacillin-Tazobactam in a Translational Rat Model.

Clinical studies have reported additive nephrotoxicity associated with the combination of vancomycin (VAN) and piperacillin-tazobactam (TZP). This study assessed differences in glomerular filtration rate (GFR) and urinary biomarkers between rats receiving VAN and those receiving VAN + TZP. Male Sprague-Dawley rats (n = 26) were randomized to receive 96 h of intravenous VAN at 150 mg/kg/day, intraperitoneal TZP at 1,400 mg/kg/day, or VAN + TZP. Kidney function was evaluated using fluorescein-isothiocyanate sinistrin and a transdermal sensor to estimate real-time glomerular filtration rate (GFR). Kidney injury was evaluated via urinary biomarkers, including kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to a saline control, only rats in the VAN group showed significant declines in GFR by day 4 (-0.39 mL/min/100 g body weight; 95% confidence interval [CI], -0.68 to -0.10; P = 0.008). When the VAN + TZP and VAN alone treatment groups were compared, significantly higher urinary KIM-1 marginal linear predictions were observed in the VAN alone group on day 1 (18.4 ng; 95% CI, 1.4 to 35.3; P = 0.03), day 2 (27.4 ng; 95% CI, 10.4 to 44.3; P = 0.002), day 3 (18.8 ng; 95% CI, 1.9 to 35.8; P = 0.03), and day 4 (23.2 ng; 95% CI, 6.3 to 40.2; P = 0.007). KIM-1 was the urinary biomarker that most correlated with decreasing GFR on day 3 (Spearman's rho, -0.45; P = 0.022) and day 4 (Spearman's rho, -0.41; P = 0.036). Kidney function decline and increased KIM-1 were observed among rats that received VAN only but not those that received TZP or VAN + TZP. The addition of TZP to VAN does not worsen kidney function or injury in our translational rat model.

Vancomycin Pharmacokinetics in a Pregnancy Rat Model.

Vancomycin usage is often unavoidable in pregnant patients; however, literature suggests vancomycin can cross the placental barrier and reach the fetus. Understanding the mass transit of vancomycin to the fetus is important in pregnancy. We aimed to (i) identify a relevant population pharmacokinetic (PK) model for vancomycin in pregnancy and (ii) estimate PK parameters and describe the mass transit of vancomycin from mother to pup kidneys. Pregnant Sprague-Dawley rats (i.e., trimester 1 and trimester 3) received 250 mg/kg vancomycin once daily for three days through intravenous injection via an internal jugular vein catheter. Vancomycin concentrations in maternal plasma and pup kidneys were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple compartment models were fitted and assessed using a nonparametric approach with Pmetrics. A total of 10 vancomycin-treated rats and 48 pups contributed PK data. A 3-compartment model adjusted for trimester fit the data well (maternal plasma Bayesian, observed versus predicted R2 = 0.978; pup kidney Bayesian, observed versus predicted R2 = 0.999). The mean rate constant for vancomycin mass transit to the pup kidney was 0.72 h-1 for trimester 1 dams and 0.75 h-1 for trimester 3 dams. Median vancomycin concentrations in pup kidneys from trimester 3 were significantly higher than those in trimester 1 (8.62 versus 0.36 µg/mL, P < 0.001). Vancomycin transited to the fetus from the mother and was; kidney accumulation differed by trimester. This model may be useful for a translational understanding of vancomycin distribution in pregnancy to ensure efficacious and safe doses to both mother and fetus.

Cefepime Precision Dosing Tool: from Standard to Precise Dose Using Nonparametric Population Pharmacokinetics.

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate a cefepime population pharmacokinetic (PK) model and integrate it into a precision dosing tool for implementation. Two data sets (680 patients) were used to build the cefepime PK model in Pmetrics, and three data sets (34 patients) were used for the validation. A separate application data set (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 h-1 (adults) and 0.96 h-1 (children), the central volume of distribution was 13.85 L, and the rate of transfer from the central to the peripheral compartments was 1.22 h-1 and from the peripheral to the central compartments was 1.38 h-1. After integration in BestDose, the observed versus predicted cefepime concentration fit using the application data set was excellent (R2 > 0.98), and the median difference between what was observed and what BestDose predicted on a second occasion was 4%. For the OID, cefepime at a 0.5- to 1-g 4-h infusion every 8 to 24 h (q8 to 24 h) with a CrCl of <70 mL/min was needed to achieve a target range of free trough:MIC 1 to 4 at a MIC of 8 mg/L, while continuous infusion was needed for higher CrCl and weight values. In conclusion, we developed and validated a cefepime model for clinical application. The model was integrated in a precision dosing tool for implementation, and the median concentration prediction bias was 4%. The OID algorithm was provided.

Does calculation method matter for targeting vancomycin area under the curve?

OBJECTIVES: To assess differences in vancomycin AUC estimates from two common, clinically applied first-order pharmacokinetic equation methods compared with Bayesian estimates. METHODS: A cohort of patients who received vancomycin and therapeutic drug monitoring was studied. First-order population pharmacokinetic equations were used to guide initial empirical dosing. After receipt of the first dose, patients had peak and trough serum levels drawn and steady-state AUC was estimated using first-order pharmacokinetic equations as standard care. We subsequently created a Bayesian model and used individual Empirical Bayes Estimates to precisely calculate vancomycin AUC24-48, AUC48-72 and AUC72-96 in this cohort. AUC at steady state (AUCSS) differences from the first-order methods were compared numerically and categorically (i.e. below, within or above 400-600 mg·h/L) to Bayesian AUCs, which served as the gold standard. RESULTS: A total of 65 adult inpatients with 409 plasma samples were included in this analysis. A two-compartment intravenous infusion model with first-order elimination fit the data well. The mean of Bayesian AUC24-48 was not significantly different from AUC estimates from the two first-order pharmacokinetic equation methods (P = 0.68); however, Bayesian AUC48-72 and Bayesian AUC72-96 were both significantly different when compared with both first-order pharmacokinetic equation methods (P < 0.01 for each). At the patient level, categorical classifications of AUC estimates from the two first-order pharmacokinetic equation methods differed from categorizations derived from the Bayesian calculations. Categorical agreement was ∼50% between first-order and Bayesian calculations, with declining categorical agreement observed with longer treatment courses. Differences in categorical agreement between calculation methods could potentially result in different dose recommendations for the patient. CONCLUSIONS: Bayesian-calculated AUCs between 48-72 and 72-96 h intervals were significantly different from first-order pharmacokinetic method-estimated AUCs at steady state. The various calculation methods resulted in different categorical classification, which could potentially lead to erroneous dosing adjustments in approximately half of the patients.

Individual target pharmacokinetic/pharmacodynamic attainment rates among meropenem-treated patients admitted to the ICU with hospital-acquired pneumonia.

OBJECTIVES: Critical illness reduces ß-lactam pharmacokinetic/pharmacodynamic (PK/PD) attainment. We sought to quantify PK/PD attainment in patients with hospital-acquired pneumonia. METHODS: Meropenem plasma PK data (n = 70 patients) were modelled, PK/PD attainment rates were calculated for empirical and definitive targets, and between-patient variability was quantified [as a coefficient of variation (CV%)]. RESULTS: Attainment of 100% T>4×MIC was variable for both empirical (CV% = 92) and directed (CV% = 33%) treatment. CONCLUSIONS: Individualization is required to achieve suggested PK/PD targets in critically ill patients.

In Vivo Targeting of Escherichia coli with Vancomycin-Arginine.

The ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to Gram-negative bacteria was investigated. Its MIC towards Escherichia coli, including ß-lactamase expressing Ambler classes A, B, and D, was 8 to 16 µg/ml. Addition of 8 times the MIC of V-r to E. coli was acutely bactericidal and associated with a low frequency of resistance (<2.32 × 10-10). In vivo, V-r markedly reduced E. coli burden by >7 log10 CFU/g in a thigh muscle model. These data warrant further development of V-r in combatting E. coli, including resistant forms.

The Pharmacodynamic-Toxicodynamic Relationship of AUC and Cmax in Vancomycin-Induced Kidney Injury in an Animal Model.

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received intravenous (i.v.) vancomycin doses of 300 mg/kg/day and 400 mg/kg/day, divided into once-, twice-, three-times-, or four-times-daily doses (i.e., QD, BID, TID, or QID) over 24 h. Up to 8 samples plus a terminal sample were drawn during the 24-h dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration from 0 to 24 h [Cmax0-24]) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed versus predicted concentrations; R2 = 0.96). KIM-1 values were greater in QD and BID groups (P for QD versus TID, <0.002; P for QD versus QID, <0.004; P for BID versus TID, <0.002; and P for BID versus QID, <0.004). Exposure-response relationships were observed between KIM-1 versus Cmax0-24 and AUC0-24 (R2 = 0.7 and 0.68). Corrected Akaike's information criterion showed Cmax0-24 as the most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (-5.28 versus -1.95). While PK-TD indices are often intercorrelated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.

Of Rats and Men: a Translational Model To Understand Vancomycin Pharmacokinetic/Toxicodynamic Relationships.

Vancomycin area under the concentration curve (AUC) is known to predict vancomycin-induced acute kidney injury (AKI). Data were analyzed from a rat model (n = 48) and two prospective clinical studies (PROVIDE [n = 263] and CAMERA2 [n = 291]). A logit-link model was used to calculate the multiplicative factors between the probability of AKI from clinical studies and in the rat. The rat was 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 and 794.3 mg·h/liter, respectively.

The case for precision dosing: medical conservatism does not justify inaction.

The need for precision dosing has been challenged on the basis of insufficient evidence. Herein, we argue that adequate evidence exists to conduct therapeutic drug monitoring (TDM) and precisely target antibiotic exposures. While achievement of any antibiotic concentration does not guarantee efficacy sans toxicity for any single patient, stochastic control optimizes the probability of achieving favourable responses across patients. We argue that variability in targets (such as the organism's MIC) can be considered with models. That is, complexity alone does not relegate the decision-making framework to 'clinician intuition'. We acknowledge the exposure-response relationships are modified by patient-specific factors (other drugs, baseline organ functional status etc.) and describe how precision dosing can inform clinical decision making rather than protocolize it. Finally, we call for randomized, controlled trials; however, we suggest that these trials are not necessary to make TDM standard of care for multiple classes of antibiotics.

Precision dosing of vancomycin: in defence of AUC-guided therapy in children.

In 2020, new vancomycin guidelines were released, recommending the transition from trough-based to AUC24 monitoring for adult and paediatric patients. Given the resources required to achieve this transition, there has been debate about the costs and benefits of AUC24-based monitoring. A recent narrative review of vancomycin therapeutic drug monitoring in paediatrics claims to have uncovered the methodological weaknesses of the data that informed the guidelines and advises against premature adoption of AUC24-guided monitoring. In this article, we present supporting arguments for AUC24-guided monitoring in children, which include that: (i) troughs alone are inadequate surrogates for AUC24; (ii) vancomycin-associated nephrotoxicity has significant consequences that warrant optimization of dosing; (iii) a substantial portion of children receiving vancomycin are at high risk for poor outcomes and deserve targeted monitoring; and (iv) limited efficacy data in support of AUC24 is not a justification to revert to a less supported monitoring approach.

Microsampling Assays for Pharmacokinetic Analysis and Therapeutic Drug Monitoring of Antimicrobial Drugs in Children: A Critical Review.

BACKGROUND: With the increasing prevalence of multidrug resistant organisms, therapeutic drug monitoring (TDM) has become a common tool for assuring the safety and efficacy of antimicrobial drugs at higher doses. Microsampling techniques, including dried blood spotting (DBS) and volumetric absorptive microsampling (VAMS), are attractive tools for TDM and pediatric clinical research. For microsampling techniques to be a useful tool for TDM, it is necessary to establish the blood-plasma correlation and the therapeutic window of antimicrobial drugs in the blood. METHODS: DBS involves the collection of small volumes of blood (30-50 µL per spot) on a filter paper, whereas VAMS allows the accurate and precise collection of a fixed volume of blood (10-30 µL) with microsampling devices. One of the major advantages of VAMS is that it reduces or eliminates the volumetric blood hematocrit (HCT) bias associated with DBS. Liquid chromatography with tandem mass spectrometry is a powerful tool for the accurate quantification of antimicrobial drugs from small volumes of blood specimens. RESULTS: This review summarizes the recent liquid chromatography with tandem mass spectrometry assays that have used DBS and VAMS approaches for quantifying antimicrobial drugs. Sample collection, extraction, validation outcomes, including the interassay and intra-assay accuracy and precision, recovery, stability, and matrix effect, as well as the clinical application of these assays and their potential as tools of TDM are discussed herein. CONCLUSIONS: Microsampling techniques, such as VAMS, provide an alternative approach to traditional plasma sample collection for TDM.