Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for Phase IIa and Phase III evaluation.

PURPOSE: A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections. METHODS: Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min). Achievement of > 90% joint PTA and the impact of differential renal clearance were considerations in dose selection. RESULTS: Iteration 1 simulations for Phase I/IIa dose selection/modification demonstrated that 3-h and continuous infusions provide comparable PTA; avibactam dose drives joint PTA within clinically relevant exposure targets; and loading doses support more rapid joint target attainment. An aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h were selected for further evaluation. Iteration 2 simulations using expanded PK models supported an alteration to the regimen (500/167 mg loading; 1500/500 mg q6h maintenance 3-h infusions for CrCL > 50 mL/min) and selection of doses for renal impairment for Phase IIa/III clinical studies. CONCLUSION: A loading dose plus 3-h maintenance infusions of aztreonam-avibactam in a 3:1 fixed ratio q6h optimizes joint PTA. These analyses supported dose selection for the aztreonam-avibactam Phase III clinical program. CLINICAL TRIAL REGISTRATION: NCT01689207; NCT02655419; NCT03329092; NCT03580044.

How to Dose Vancomycin in Overweight and Obese Patients with Varying Renal (Dys)function in the Novel Era of AUC 400-600 mg·h/L-Targeted Dosing.

BACKGROUND AND OBJECTIVE: The latest vancomycin guideline recommends area under the curve (AUC)-targeted dosing and monitoring for efficacy and safety. However, guidelines for AUC-targeted starting dosing in patients with obesity and/or renal insufficiency are currently lacking. This study quantifies the pharmacokinetics (PK) of vancomycin in this population and provides AUC-targeted dosing recommendations. METHODS: Vancomycin concentrations (n = 1188) from therapeutic drug monitoring of 210 overweight and obese patients with varying degrees of renal (dys)function from the ward (74.8%) and intensive care unit (ICU, 25.2%) were pooled with published rich concentration-time data (n = 207) from 20 (morbidly) obese subjects undergoing bariatric surgery. A population model was developed using NONMEM 7.4. Stochastic simulations were performed to design dosing guidelines targeting an AUC24 between 400-600 mg·h/L. RESULTS: Vancomycin clearance (CL) was found to increase linearly with total bodyweight and with renal function (CKD-EPI) in a power relation. Additionally, CL proved 15.5% lower in ICU patients. Our model shows that, to reach the target AUC between 400 and 600 mg·h/L in the first 48 h, two loading doses are required for both continuous infusion and intermittent dosing regimens. Maintenance doses were found to require adjustment for total bodyweight, renal function, and ICU admission status. With this guideline, the median AUC24 is well within the target from the start of the treatment onwards. CONCLUSIONS: To achieve safe and effective vancomycin exposure for maintenance doses in overweight and obese patients, renal function, total bodyweight, and ICU admission status should be taken into account. TRIAL REGISTRATION: The AMIGO trial was registered in the Dutch Trial Registry [NTR6058].

Dose Individualization of Cefepime for Febrile Neutropenia in Patients With Lymphoma or Multiple Myeloma: Implications for Therapeutic Drug Monitoring.

BACKGROUND: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma. METHODS: This prospective study enrolled 16 patients receiving cefepime at a dose of 2 g every 12 hours. Unbound concentrations were determined at 0.5 hours, 7.2 hours [at the 60% time point of the 12 hours administration interval (C7.2h)], and 11 hours (trough concentration) after the first infusion (rate: 2 g/h). The primary and secondary end points were the predictive performance of the area under the unbound concentration-time curve (AUC unbound ) and the effect of unbound cefepime pharmacokinetic parameters on clinical response, respectively. RESULTS: The mean (SD) AUC unbound was 689.7 (226.6) mcg h/mL, which correlated with C7.2h (R 2 = 0.90), and the Bayesian posterior AUC unbound using only the trough concentration (R 2 = 0.66). Although higher exposure was more likely to show a better clinical response, each parameter did not indicate a statistical significance between positive and negative clinical responses ( P = 0.0907 for creatinine clearance (Ccr), 0.2523 for C7.2h, 0.4079 for trough concentration, and 0.1142 for AUC unbound ). Cutoff values were calculated as 80.2 mL/min for Ccr (sensitivity: 0.889, specificity: 0.714), 18.6 mcg/mL for C7.2h (sensitivity: 0.571, specificity: 1.000), and 9.2 mcg/mL for trough concentration (sensitivity: 0.571, specificity: 1.000). When aiming for a time above 100% the minimum inhibitory concentration, both continuous infusion of 4 g/d and intermittent infusion of 2 g every 8 hours achieved a probability of approximately 100% at a minimum inhibitory concentration of 8 mcg/mL. CONCLUSIONS: Therapeutic drug monitoring by sampling at C7.2h or trough can facilitate rapid dose optimization. Continuous infusion of 4 g/d was recommended. Intermittent dosing of 2 g every 8 hours was alternatively suggested for patients with a Ccr of 60-90 mL/min.

Ceftolozane-Tazobactam against Pseudomonas aeruginosa Cystic Fibrosis Clinical Isolates in the Hollow-Fiber Infection Model: Challenges Imposed by Hypermutability and Heteroresistance.

Pseudomonas aeruginosa remains a challenge in chronic respiratory infections in cystic fibrosis (CF). Ceftolozane-tazobactam has not yet been evaluated against multidrug-resistant hypermutable P. aeruginosa isolates in the hollow-fiber infection model (HFIM). Isolates CW41, CW35, and CW44 (ceftolozane-tazobactam MICs of 4, 4, and 2 mg/L, respectively) from adults with CF were exposed to simulated representative epithelial lining fluid pharmacokinetics of ceftolozane-tazobactam in the HFIM. Regimens were continuous infusion (CI; 4.5 g/day to 9 g/day, all isolates) and 1-h infusions (1.5 g every 8 hours and 3 g every 8 hours, CW41). Whole-genome sequencing and mechanism-based modeling were performed for CW41. CW41 (in four of five biological replicates) and CW44 harbored preexisting resistant subpopulations; CW35 did not. For replicates 1 to 4 of CW41 and CW44, 9 g/day CI decreased bacterial counts to <3 log10 CFU/mL for 24 to 48 h, followed by regrowth and resistance amplification. Replicate 5 of CW41 had no preexisting subpopulations and was suppressed below ~3 log10 CFU/mL for 120 h by 9 g/day CI, followed by resistant regrowth. Both CI regimens reduced CW35 bacterial counts to <1 log10 CFU/mL by 120 h without regrowth. These results corresponded with the presence or absence of preexisting resistant subpopulations and resistance-associated mutations at baseline. Mutations in ampC, algO, and mexY were identified following CW41 exposure to ceftolozane-tazobactam at 167 to 215 h. Mechanism-based modeling well described total and resistant bacterial counts. The findings highlight the impact of heteroresistance and baseline mutations on the effect of ceftolozane-tazobactam and limitations of MIC to predict bacterial outcomes. The resistance amplification in two of three isolates supports current guidelines that ceftolozane-tazobactam should be utilized together with another antibiotic against P. aeruginosa in CF.

Effects of a 10% dimethyl sulfoxide solution on radiocarpal joint amikacin pharmacokinetics during intravenous regional limb perfusion in standing sedated horses.

OBJECTIVE: To determine the effect of a 10% dimethyl sulfoxide (DMSO) solution on the peak concentration (CMAX ) of amikacin in the radiocarpal joint (RCJ) during intravenous regional limb perfusion (IVRLP) compared with 0.9% NaCl. STUDY DESIGN: Randomized crossover study. ANIMALS: Seven healthy adult horses. METHODS: The horses underwent IVRLP with 2 g of amikacin sulfate diluted to 60 mL using a 10% DMSO or 0.9% NaCl solution. Synovial fluid was collected from the RCJ at 5, 10, 15, 20, 25, and 30 minutes after IVRLP. The wide rubber tourniquet placed on the antebrachium was removed after the 30 min sample. Amikacin concentrations were quantified by a fluorescence polarization immunoassay. The mean CMAX and time to peak concentration (TMAX ) of amikacin within the RCJ were determined. A one-sided paired t-test was used to determine the differences between treatments. The significance level was p < .05. RESULTS: The mean ± SD CMAX in the DMSO group was 1361.8 ± 593 µg/mL and in the 0.9% NaCl group it was 860 ± 481.6 µg/mL (p = .058). Mean TMAX using the 10% DMSO solution was 23 and 18 min using the 0.9% NaCl perfusate (p = .161). No adverse effects were associated with use of the 10% DMSO solution. CONCLUSION: Although there were higher mean peak synovial concentrations using the 10% DMSO solution no difference in synovial amikacin CMAX between perfusate type was detected (p = .058). CLINICAL SIGNIFICANCE: Use of a 10% DMSO solution in conjunction with amikacin during IVRLP is a feasible technique and does not negatively affect the synovial amikacin levels achieved. Further research is warranted to determine other effects of using DMSO during IVRLP.

Cordycepin: A review of strategies to improve the bioavailability and efficacy.

Cordycepin is a bioactive compound extracted from Cordyceps militaris. As a natural antibiotic, cordycepin has a wide variety of pharmacological effects. Unfortunately, this highly effective natural antibiotic is proved to undergo rapid deamination by adenosine deaminase (ADA) in vivo and, as a consequence, its half-life is shortened and bioavailability is decreased. Therefore, it is of critical importance to work out ways to slow down the deamination so as to increase its bioavailability and efficacy. This study reviews recent researches on a series of aspects of cordycepin such as the bioactive molecule's pharmacological action, metabolism and transformation as well as the underlying mechanism, pharmacokinetics and, particularly, the methods for reducing the degradation to improve the bioavailability and efficacy. It is drawn that there are three methods that can be applied to improve the bioavailability and efficacy: to co-administrate an ADA inhibitor and cordycepin, to develop more effective derivatives via structural modification, and to apply new drug delivery systems. The new knowledge can help optimize the application of the highly potent natural antibiotic-cordycepin and develop novel therapeutic strategies.

Evaluation of the Impact of Comorbidities on Omadacycline Pharmacokinetics.

Omadacycline is approved in the United States for the treatment of patients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections. Analyses were undertaken to evaluate pharmacokinetic differences among subjects or patients stratified by comorbidities. Differences in clearance by smoking status, history of diabetes mellitus, chronic lung disease, hypertension, heart failure, or coronary artery disease were evaluated using a Welch two-sample t test. Smoking was the only significant comorbidity after correction for sex, with a clinically insignificant difference of 13%. Omadacycline dose adjustments based on these comorbidities do not appear to be warranted.

Model-Informed Clinical Practice - Determining an Appropriate Ampicillin-Sulbactam Redosing Regimen in Surgical Patients by Utilizing Population Pharmacokinetics and Target Attainment Analysis.

In the current study, population pharmacokinetic (PK) of ampicillin-sulbactam was performed based on the clinical pharmacokinetics data collected from a prospective study conducted in 40 surgical patients undergoing prolonged surgery where antibiotic redosing was implemented. A population PK model was successfully developed to characterize the disposition of ampicillin and sulbactam. The final models were two-compartment models for both drugs, with creatinine clearance and heart failure affecting clearance and body surface area having an impact on the central volume of distribution of both ampicillin and sulbactam. Comprehensive Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of 24 different redosing scenarios. Simulation results indicated that the ampicillin-sulbactam 2-h redosing scheme recommended by ASHP guidelines is likely too conservative given that 3-g dose (2-g ampicillin/1-g sulbactam) with 4-h redosing interval can reach the breakpoint of 2 mg/L for ampicillin in all populations even with the aggressive pharmacokinetic/pharmacodynamic (PK/PD) target of 100% fT > MIC. With the target 50% fT > MIC, all redosing schemes evaluated, including the 8-h redosing scenario, are predicted to be able to reach the breakpoint of 64 mg/L in all patients. According to our findings, redosing of ampicillin-sulbactam should be every 4 h instead of the currently recommended 2-h redosing schedule. Our PTA results should inform future updates to existing general antibiotic redosing guidelines; and, when used in combination with the availability of institution- and/or unit-specific ampicillin susceptibility patterns, our PTA results may be used to customize SSI prophylaxis redosing recommendations for ampicillin-sulbactam at individual hospitals.

Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis.

BACKGROUND AND OBJECTIVE: Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations. METHODS: Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureus including patients undergoing hemodialysis. A total of 339 serum total and 329 unbound daptomycin concentrations were used for model construction. RESULTS: Total and unbound daptomycin concentration was explained by a model that assumed first-order distribution with two compartments, and first-order elimination. Normal fat body mass was identified as covariates. Renal function was incorporated as a linear function of renal clearance and independent non-renal clearance. The unbound fraction was estimated to be 0.066 with a standard albumin of 45 g/L and standard creatinine clearance of 100 mL/min. Simulated unbound daptomycin concentration was compared with minimum inhibitory concentration as a measure of clinical effectiveness and exposure-level-related induction of creatine phosphokinase elevation. The recommended doses were 4 mg/kg for patients with severe renal function [creatinine clearance (CLcr) ≤ 30 mL/min] and 6 mg/kg for patients with mild to moderate renal function (CLcr > 30 and ≤ 60 mL/min). A simulation indicated that dose adjusted by body weight and renal function improved target attainment. CONCLUSIONS: This population pharmacokinetics model for unbound daptomycin could help clinicians to select the appropriate dose regimen for patients undergoing daptomycin treatment and reduce associated adverse effects.

Development and Evaluation of a Height-Based Tobramycin Initial Dosing Nomogram for the Treatment of Adult Cystic Fibrosis Pulmonary Exacerbations.

ABSTRACT: Tobramycin is widely used to treat pulmonary exacerbations of cystic fibrosis. Height has been previously found to be significantly more predictive of tobramycin pharmacokinetics than body weight. This study aimed to develop a height-based initial dosing nomogram and evaluate its performance in peak concentration (Cmax) precision relative to standard and fixed dosing. Monte Carlo simulations were performed to develop a nomogram representing the doses required to reach Cmax targets at different heights. Cmax data observed at 2 clinical centers [McGill University Health Centre (MUHC) and Institut universitaire de cardiologie et pneumologie de Québec (IUCPQ-UL)] were compared with population-predicted Cmax using the doses derived from the nomogram alongside a fixed dose. Height-based dosing resulted in significantly less variable-predicted Cmax values [coefficient of variation (CV) MUHC = 15.7% and IUCPQ-UL = 10.8%] than the Cmax values observed in clinical practice (CV MUHC = 30.0% and CV IUCPQ-UL = 26.9%) and predicted Cmax values obtained from a fixed dose (CV MUHC = 21.2% and CV IUCPQ-UL = 16.3%). An initial dosing nomogram was developed to help reduce pharmacokinetic variability in the observed Cmax. More precise dosing would allow for better clinical outcomes in adult patients with cystic fibrosis.

Pharmacokinetic Alterations Associated with Critical Illness.

Haemodynamic, metabolic, and biochemical derangements in critically ill patients affect drug pharmacokinetics and pharmacodynamics making dose optimisation particularly challenging. Appropriate therapeutic dosing depends on the knowledge of the physiologic changes caused by the patient's comorbidities, underlying disease, resuscitation strategies, and polypharmacy. Critical illness will result in altered drug protein binding, ionisation, and volume of distribution; it will also decrease oral drug absorption, intestinal and hepatic metabolism, and renal clearance. In contrast, the resuscitation strategies and the use of vasoactive drugs may oppose these effects by leading to a hyperdynamic state that will increase blood flow towards the major organs including the brain, heart, kidneys, and liver, with the subsequent increase of drug hepatic metabolism and renal excretion. Metabolism is the main mechanism for drug clearance and is one of the main pharmacokinetic processes affected; it is influenced by patient-specific factors, such as comorbidities and genetics; therapeutic-specific factors, including drug characteristics and interactions; and disease-specific factors, like organ dysfunction. Moreover, organ support such as mechanical ventilation, renal replacement therapy, and extracorporeal membrane oxygenation may contribute to both inter- and intra-patient variability of drug pharmacokinetics. The combination of these competing factors makes it difficult to predict drug response in critically ill patients. Pharmacotherapy targeted to therapeutic goals and therapeutic drug monitoring is currently the best option for the safe care of the critically ill. The aim of this paper is to review the alterations in drug pharmacokinetics associated with critical illness and to summarise the available evidence.

Superiority of ceftazidime off-label high-dose regimen in PK/PD target attainment during treatment of extensively drug-resistant Pseudomonas aeruginosa infections in cancer patients.

AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.

Penetration of Vancomycin into Noninfected Bone in Patients Undergoing Total Joint Arthroplasty Evaluated by a Minimal Physiologically Based Population Pharmacokinetic Modeling Approach.

Arthroplasty is a healthcare priority and represents high volume, high cost surgery. Periprosthetic joint infection (PJI) results in significant mortality, thus it is vital that the risk for PJI is minimized. Vancomycin is recommended for surgical prophylaxis in total joint arthroplasty (TJA) by current clinical practice guidelines endorsed by the Infectious Diseases Society of America. This study aimed to develop a new assay to determine vancomycin concentrations in serum and bone, and a minimal physiologically based population PK (mPBPK) model to evaluate vancomycin bone penetration in noninfected patients. Eleven patients undergoing TJA received 0.5-2.0 g intravenous vancomycin over 12-150 min before surgery. Excised bone specimens and four blood samples were collected per patient. Bone samples were pulverized under liquid nitrogen using a cryogenic mill. Vancomycin concentrations in serum and bone were analyzed by liquid chromatography-tandem mass spectrometry and subjected to mPBPK modeling. Vancomycin serum and bone concentrations ranged from 9.30 to 86.6 mg/L, and 1.94-37.0 mg/L, respectively. Average bone to serum concentration ratio was 0.41 (0.16-1.0) based on the collected samples. The population mean total body clearance was 2.12L/h/kg0.75. Inclusion of total body weight as a covariate substantially decreased interindividual variability in clearance. The bone/blood partition coefficient (Kpbone) was estimated at 0.635, reflecting the average bone/blood concentration ratio at steady-state. The model predicted median ratio of vancomycin area under the curve (AUC) for bone/AUC for serum was 44%. Observed vancomycin concentrations in bone were overall consistent with perfusion-limited distribution from blood to bone. An mPBPK model overall well described vancomycin concentrations in serum and bone.

A simple label-free method reveals bacterial growth dynamics and antibiotic action in real-time.

Understanding the response of bacteria to environmental stress is hampered by the relative insensitivity of methods to detect growth. This means studies of antibiotic resistance and other physiological methods often take 24 h or longer. We developed and tested a scattered light and detection system (SLIC) to address this challenge, establishing the limit of detection, and time to positive detection of the growth of small inocula. We compared the light-scattering of bacteria grown in varying high and low nutrient liquid medium and the growth dynamics of two closely related organisms. Scattering data was modelled using Gompertz and Broken Stick equations. Bacteria were also exposed meropenem, gentamicin and cefoxitin at a range of concentrations and light scattering of the liquid culture was captured in real-time. We established the limit of detection for SLIC to be between 10 and 100 cfu mL-1 in a volume of 1-2 mL. Quantitative measurement of the different nutrient effects on bacteria were obtained in less than four hours and it was possible to distinguish differences in the growth dynamics of Klebsiella pneumoniae 1705 possessing the BlaKPC betalactamase vs. strain 1706 very rapidly. There was a dose dependent difference in the speed of action of each antibiotic tested at supra-MIC concentrations. The lethal effect of gentamicin and lytic effect of meropenem, and slow bactericidal effect of cefoxitin were demonstrated in real time. Significantly, strains that were sensitive to antibiotics could be identified in seconds. This research demonstrates the critical importance of improving the sensitivity of bacterial detection. This results in more rapid assessment of susceptibility and the ability to capture a wealth of data on the growth dynamics of bacteria. The rapid rate at which killing occurs at supra-MIC concentrations, an important finding that needs to be incorporated into pharmacokinetic and pharmacodynamic models. Importantly, enhanced sensitivity of bacterial detection opens the possibility of susceptibility results being reportable clinically in a few minutes, as we have demonstrated.

Nitrofurantoin plasma- and urine exposure in eight healthy beagle dogs following standard nitrofurantoin dosing regimen.

Bacterial cystitis is common in dogs and is usually treated with antibiotics. Nitrofurantoin is used for treatment of bacterial cystitis in humans and might provide a feasible treatment option in dogs. The aim of this study was to investigate the nitrofurantoin plasma concentration-time course and potential adverse effects in dogs. Nitrofurantoin (4.4-5.0 mg/kg) was administered orally to eight healthy beagles every 8 h for five days before repeated plasma and urine samples were collected. An additional four beagles served as untreated controls. The nitrofurantoin plasma and urine concentrations were measured using ultra high precision liquid chromatography coupled to tandem mass-spectrometry and further analysed using a non-compartmental pharmacokinetic model. In plasma, the median Cmax was 2.1 µg/mL, tmax was 2 h, the terminal rate constant was 0.9 per h and the terminal half-life was 0.8 h. In urine, median Cmax was 56 µg/mL, tmax was 1 h and the terminal half-life was 4.3 h. No adverse effects were observed clinically or in haematology or biochemistry. The data presented in this study combined with in vitro sensitivity data from common urine pathogens and the lack of observed adverse effects suggest that nitrofurantoin in a standard dosing regimen could be effective in sporadic bacterial cystitis treatment in dogs. Further clinical studies are highly warranted to verify the effectiveness in clinical cases.

Pharmacokinetic/pharmacodynamic parameters of vancomycin for predicting clinical outcome of enterococcal bacteremia.

PURPOSE: To find pharmacokinetic/pharmacodynamic parameters of vancomycin associated with the optimal outcome of severe infection due to Enterococcus species. METHODS: We retrospectively reviewed enterococcal bacteremia cases treated with vancomycin from January 2015 to December 2020. The primary outcome was 30-day mortality. We calculated cutoff values of the ratio of vancomycin area under the concentration-time curve over 24 h to the minimum inhibitory concentration (AUC24/MIC) and trough concentration (Ctrough) during the initial 72 h of treatment. The optimal cutoff value was determined using the Youden index. Binary variables created based on these cutoffs were further assessed using multivariable analysis. RESULTS: A total of 65 patients were included. The majority (87.7%) had solid or hematologic malignancies. Thirty-day mortality and nephrotoxicity occurred in nine (13.4%) and 14 (21.5%) patients, respectively. Both vancomycin AUC24/MIC and Ctrough showed fair performance in predicting 30-day mortality (AUC of receiver-operator curve for AUC24/MIC, 0.712; 95% confidence interval [CI] 0.539-0.886; AUC for Ctrough, 0.760; 95% CI 0.627-0.892; pairwise AUC comparison: p = 0.570). Ctrough ≥ 13.94 µg/mL, but not AUC24/MIC ≥ 504, had a significant association with 30-day mortality after adjusting for confounders (odds ratio, 8.40; 95% CI 1.60-86.62; p = 0.010). CONCLUSION: Mean Ctrough ≥ 13.94 µg/mL during the initial 72 h was associated with higher 30-day mortality in enterococcal bacteremia. Further studies are warranted to elucidate optimal pharmacokinetic targets for enterococcal bacteremia.

Tigecycline Soft Tissue Penetration in Obese and Non-obese Surgical Patients Determined by Using In Vivo Microdialysis.

BACKGROUND AND OBJECTIVE: Tigecycline, a broad-spectrum glycylcycline antibiotic, is approved for use at a fixed dose irrespective of body weight. However, its pharmacokinetics may be altered in obesity, which would impact on the antibiotic's effectiveness. The objective of this study was to investigate the plasma and subcutaneous tissue concentrations of tigecycline in obese patients compared with those in a non-obese control group. METHODS: Fifteen obese patients (one class II and 14 class III) undergoing bariatric surgery and 15 non-obese patients undergoing intra-abdominal surgery (mainly tumour resection) received a single dose of 50 or 100 mg tigecycline as an intravenous short infusion. Tigecycline concentrations were measured up to 8 h after dosing in plasma (total concentration), in ultrafiltrate of plasma (free concentration), and in microdialysate from subcutaneous tissue, respectively. RESULTS: In obese patients, total peak plasma concentration (1.31 ± 0.50 vs 2.27 ± 1.40 mg/L) and the area under the concentration-time curve from 0 to 8 h (AUC8h,plasma: 2.15 ± 0.42 vs 2.74 ± 0.73 h⋅mg/L), as normalized to a 100 mg dose, were significantly lower compared with those of non-obese patients. No significant differences were observed regarding the free plasma concentration, as determined by ultrafiltration, or the corresponding AUC8h (fAUC8h,plasma). Concentrations in interstitial fluid (ISF) of subcutaneous tissue were lower than the free plasma concentrations in both groups, and they were lower in obese compared to non-obese patients: the AUC8h in ISF (AUC8h,ISF) was 0.51 ± 0.22 h⋅mg/L in obese and 0.79 ± 0.23 h⋅mg/L in non-obese patients, resulting in a relative tissue drug exposure (AUC8h,ISF/fAUC8h,plasma) of 0.38 ± 0.19 and 0.63 ± 0.24, respectively. CONCLUSION: Following a single dose of tigecycline, concentrations in the ISF of subcutaneous adipose tissue are decreased in heavily obese subjects, calling for an increased loading dose. EU CLINICAL TRIALS REGISTRATION NUMBER: EudraCT No. 2012-004383-22.

Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients.

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.

Suboptimal Beta-Lactam Therapy in Critically Ill Children: Risk Factors and Outcome.

OBJECTIVES: In critically ill children, severely altered pharmacokinetics may result in subtherapeutic ß-lactam antibiotic concentrations when standard pediatric dosing regimens are applied. However, it remains unclear how to recognize patients most at risk for suboptimal exposure and their outcome. This study aimed to: 1) describe target attainment for ß-lactam antibiotics in critically ill children, 2) identify risk factors for suboptimal exposure, and 3) study the association between target nonattainment and clinical outcome. DESIGN: Post hoc analysis of the "Antibiotic Dosing in Pediatric Intensive Care" study (NCT02456974, 2012-2019). Steady-state trough plasma concentrations were classified as therapeutic if greater than or equal to the minimum inhibitory concentration of the (suspected) pathogen. Factors associated with subtherapeutic concentrations and clinical outcome were identified by logistic regression analysis. SETTING: The pediatric and cardiac surgery ICU of a Belgian tertiary-care hospital. PATIENTS: One hundred fifty-seven patients (aged 1 mo to 15 yr) treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam, or meropenem. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-two trough concentrations were obtained from 157 patients (median age, 1.25 yr; interquartile range, 0.4-4.2 yr). Subtherapeutic concentrations were measured in 39 of 60 (65%), 43 of 48 (90%), and 35 of 49 (71%) of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam, and meropenem, respectively. Estimates of glomerular filtration rate (eGFR; 54% increase in odds for each sd increase in value, 95% CI, 0.287-0.736; p = 0.001) and the absence of vasopressor treatment (2.8-fold greater odds, 95% CI, 1.079-7.253; p = 0.034) were independently associated with target nonattainment. We failed to identify an association between antibiotic concentrations and clinical failure. CONCLUSIONS: Subtherapeutic ß-lactam concentrations are common in critically ill children and correlate with renal function. eGFR equations may be helpful in identifying patients who may require higher dosing. Future studies should focus on the impact of subtherapeutic concentrations on clinical outcome.

A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis: Assessment of Target Attainment with Extended-Interval Dosing through Simulation.

Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF <5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in >75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of Cmax >25 mg/L and AUC24 of 80-120 mg·h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.