In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC90) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation.

Antimicrobial Therapeutic Drug Monitoring in critically ill adult patients -an international perspective on access, utilisation, and barriers.

BACKGROUND: Therapeutic drug monitoring (TDM) is an effective method for individualizing antimicrobial therapy in critically ill patients. The 2021 ADMIN-ICU survey studied a wide range of intensive care unit (ICU) clinicians worldwide to gain their perspectives on antimicrobial TDM. This paper reports the responses from this survey relating to TDM access, utilisation, barriers, and clinical value. METHODS: An online survey consisted of multiple-choice questions and 5-point Likert scales. The survey examined respondent's access to minimum inhibitory concentration (MIC) results, drug assays and dosing software, as well as barriers to TDM. RESULTS: The survey included 538 clinicians from 409 hospitals in 45 countries, with 71% physicians and 29% pharmacists. Despite most respondents having access to assays, 21% and 26% of respondents lacked access to vancomycin and aminoglycosides, respectively. In lower-income countries, almost 40% reported no access. Delayed drug assay turnaround time was the most significant barrier to TDM, particularly in lower-income countries. Routine access to MIC results was unavailable for 41% of respondents, with 25% of lower-income country respondents having no access to MIC or susceptibility reports. CONCLUSIONS: This global survey indicated that consistent TDM usage is hindered by assay access in some sites, and timeliness of assay results in others. Addressing barriers to TDM, particularly in low-income countries, should be a priority to ensure equitable access to affordable TDM.

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.

Impact of humanized vancomycin infusion on kidney function and kidney injury in a translational rat model.

Allometric dose scaling aims to create isometric exposures between animals and humans and is often employed in preclinical pharmacokinetic/pharmacodynamic models. Bolus-administration with allometric scaling is the most simple and commonly used strategy in pre-clinical kidney injury studies; however, it is possible to humanize drug exposures. Currently, it is unknown if dose-matched, bolus-administration with allometric scaling results in similar outcomes compared to humanized infusions in the vancomycin induced kidney injury model. We utilized a preclinical Sprague-Dawley rat model to compare traditional allometrically-scaled, dose-matched, bolus-administration of vancomycin to an infusion-pump controlled, humanized infusion scheme to assess for differences in iohexol-measured kidney function and urinary kidney injury biomarkers. Following 24 h of vancomycin administration, rats in the humanized infusion group had equivalent area under the curve exposures to animals in the dose-matched bolus group (93.7 mg·h/L [IQR 90.2-97.2] vs. 99.5 mg·h/L [IQR 95.1-104.0], P = 0.07). No significant differences in iohexol-measured kidney function nor meaningful differences in urinary kidney injury biomarkers, kidney injury molecule-1, clusterin, and osteopontin, were detected. Administration of intravenous vancomycin as either a humanized infusion or dose-matched bolus resulted in similar vancomycin exposures. No differences in iohexol-measured GFR nor meaningful differences in urinary kidney injury biomarkers were observed among male Sprague-Dawley rats.

Flucloxacillin worsens while imipenem-cilastatin protects against vancomycin-induced kidney injury in a translational rat model.

BACKGROUND AND PURPOSE: Vancomycin is one of the most common clinical antibiotics, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received allometrically scaled (1) vancomycin, (2) flucloxacillin, (3) vancomycin + flucloxacillin, (4) vancomycin + imipenem-cilastatin or (5) saline for 4 days. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. KEY RESULTS: Urinary output increased every study day for vancomycin + flucloxacillin, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem-cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1. CONCLUSIONS AND IMPLICATIONS: Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem-cilastatin in a translational rat model. The combination of vancomycin + imipenem-cilastatin was nephroprotective.

Bioanalysis of six antibiotics from volumetric microsamples: a new tool for precision dosing in critically ill children.

Background: Volumetric absorptive microsamples (VAMS) can support pharmacokinetic / pharmacodynamic studies. We present the bioanalytical method development for the simultaneous quantification of ampicillin, cefepime, ceftriaxone, meropenem, piperacillin, tazobactam, and vancomycin from VAMS. Methods & results: Optimal extraction, chromatographic, and mass spectrometry conditions were identified. Maximum extraction recoveries included 100 µl of water for rehydration and methanol for protein precipitation. Chromatographic separation used Phenomenex Kinetex™ Polar C18 column with a mobile phase comprising water/acetonitrile with formic acid and was fully validated. Hematocrit effects were only observed for vancomycin. Samples were stable for 90 days at -80°C except for meropenem, which was stable for 60 days. Conclusion: Multiple antibiotics can be assayed from a single VAMS sample to facilitate pharmacokinetic/pharmacodynamic studies.

Impact of Various Estimated Glomerular Filtration Rate Equations on the Pharmacokinetics of Meropenem in Critically Ill Adults.

IMPORTANCE: Meropenem dosing is typically guided by creatinine-based estimated glomerular filtration rate (eGFR), but creatinine is a suboptimal GFR marker in the critically ill. OBJECTIVES: This study aimed to develop and qualify a population pharmacokinetic model for meropenem in critically ill adults and to determine which eGFR equation based on creatinine, cystatin C, or both biomarkers best improves model performance. DESIGN SETTING AND PARTICIPANTS: This single-center study evaluated adults hospitalized in an ICU who received IV meropenem from 2018 to 2022. Patients were excluded if they had acute kidney injury, were on kidney replacement therapy, or were treated with extracorporeal membrane oxygenation. Two cohorts were used for population pharmacokinetic modeling: a richly sampled development cohort (n = 19) and an opportunistically sampled qualification cohort (n = 32). MAIN OUTCOMES AND MEASURES: A nonlinear mixed-effects model was developed using parametric methods to estimate meropenem serum concentrations. RESULTS: The best-fit structural model in the richly sampled development cohort was a two-compartment model with first-order elimination. The final model included time-dependent weight normalized to a 70-kg adult as a covariate for volume of distribution (Vd) and time-dependent eGFR for clearance. Among the eGFR equations evaluated, eGFR based on creatinine and cystatin C expressed in mL/min best-predicted meropenem clearance. The mean (se) Vd in the final model was 18.2 (3.5) liters and clearance was 11.5 (1.3) L/hr. Using the development cohort as the Bayesian prior, the opportunistically sampled cohort demonstrated good accuracy and low bias. CONCLUSIONS AND RELEVANCE: Contemporary eGFR equations that use both creatinine and cystatin C improved meropenem population pharmacokinetic model performance compared with creatinine-only or cystatin C-only eGFR equations in adult critically ill patients.

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.

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.

Contemporary pharmacologic treatments of MRSA for hospitalized adults: rationale for vancomycin versus non-vancomycin therapies as first line agents.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) remains an important pathogen in the hospital setting and causes significant morbidity and mortality each year. Since the initial discovery over 60 years ago, vancomycin has remained a first-line treatment for many different types of MRSA infections. However, significant concerns related to target attainment and nephrotoxicity have spurred efforts to develop more effective agents in the last two decades. AREAS COVERED: Newer anti-MRSA antibiotics that have been approved since 2000 include linezolid, daptomycin, and ceftaroline. As clinical evidence has accumulated, these newer agents have become more frequently used, and some are now recommended as co-first-line options (along with vancomycin) in clinical practice guidelines. For this review, a scoping review of the literature was conducted to support our findings and recommendations. EXPERT OPINION: Vancomycin remains an important standard of care for MRSA infections but is limited with respect to nephrotoxicity and rapid target attainment. Newer agents such as linezolid, daptomycin, and ceftaroline have specific indications for treating different types of MRSA infections; however, newer agents also have unique attributes which require consideration during therapy.

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.

International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists: An executive summary.

Intravenous ß-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. ß-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PI) can be applied during the administration of intravenous ß-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of ß-lactam PI developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug monitoring considerations, and the use of PI ß-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of ß-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).

International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists.

Intravenous ß-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. ß-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PIs) can be applied during the administration of intravenous ß-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of PI ß-lactams developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug-monitoring considerations, and the use of PI ß-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of ß-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).

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.

Development and validation of a population pharmacokinetic model to guide perioperative tacrolimus dosing after lung transplantation.

Background: Tacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk time period. Methods: We conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group (LTOG) cohort. We derived a model in 270 patients using NONMEM (version 7.5.1) and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and multivariable analysis was developed using forward and backward stepwise selection. Performance of the final model in the validation cohort was examined with calculation of mean prediction error (PE). Results: We developed a one-compartment base model with a fixed rate absorption constant. Significant covariates in multivariable analysis were postoperative day, hematocrit, transplant type, CYP3A5 genotype, total body weight, and time-varying postoperative day, hematocrit, and CYP inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than threefold over the 14 day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95%CI 30.8%-41.9%) and a median PE of 7.2% (IQR -29.3%-70.53%). Conclusion: Postoperative day was the strongest predictor of tacrolimus exposure in the early post-lung transplant period. Future multicenter studies employing intensive sampling to examine a broad set of variables related to critical illness physiology are needed to understand determinants of clearance, volume of distribution and absorption in this population.

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.

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.

Pharmacokinetic and Biomarker Quantification Studies on Vancomycin-Loaded PEGylated Liposomes and Its Potential to Reduce Vancomycin-Induced Kidney Injury: A Rat Study.

Vancomycin is a commonly used antibiotic in hospital settings, especially against Methicillin-resistant staphylococcus aureus (MRSA). One of the major adverse events of vancomycin use in adults is kidney injury. The drug concentration, specifically the area under the concentration curve, predicts kidney injury in adults receiving vancomycin. To attempt to reduce vancomycin-induced nephrotoxicity, we have successfully encapsulated vancomycin in polyethylene glycol-coated liposomes (PEG-VANCO-lipo). We have previously carried out in vitro cytotoxicity studies on kidney cells using PEG-VANCO-lipo and found it to be minimally toxic compared to the standard vancomycin. In this study, we have dosed male adult rats with PEG-VANCO-lipo or vancomycin HCl and compared plasma vancomycin concentrations and KIM-1 as an injury biomarker in rat urine. Male Sprague Dawley rats (350 ± 10 g) were administered vancomycin (n = 6) or PEG-VANCO-lipo (n = 6) 150 mg/kg/day for three days using an IV infusion in the left jugular vein catheter. Blood was collected for plasma at 15, 30, 60, 120, 240, and 1440 min after the first and the last IV dose. Urine was collected 0-2, 2-4, 4-8, and 8-24 h after the first and the last IV infusions using metabolic cages. The animals were observed for three days after the last compound administration. Vancomycin was quantified in plasma by LC-MS/MS. Urinary KIM-1 analysis was done by using an ELISA kit. Three days after the last dose, under terminal anesthesia with IP ketamine (65-100 mg/kg) and xylazine (7-10 mg/kg), rats were euthanized. Vancomycin urine and kidney concentrations and KIM-1 were lower on day three in the PEG-Vanco-lipo group compared to the vancomycin group (p < 0.05, ANOVA and/or t-test). There was a significant reduction in plasma vancomycin concentration on day one and day three (p < 0.05, t-test) in the vancomycin group compared to the PEG-VANCO-lipo group. Vancomycin-loaded PEGylated liposomes resulted in lower levels of kidney injury, as noted by a decrease in KIM-1 values. Moreover, longer circulation in plasma with increased concentration in plasma as opposed to the kidney was observed with the PEG-VANCO-lipo group. The results indicate the high potential of PEG-VANCO-lipo in decreasing the nephrotoxicity of vancomycin clinically.

Genomics of Aminoglycoside Resistance in Pseudomonas aeruginosa Bloodstream Infections at a United States Academic Hospital.

Pseudomonas aeruginosa frequently becomes resistant to aminoglycosides by the acquisition of aminoglycoside modifying enzyme (AME) genes and the occurrence of mutations in the mexZ, fusA1, parRS, and armZ genes. We examined resistance to aminoglycosides in a collection of 227 P. aeruginosa bloodstream isolates collected over 2 decades from a single United States academic medical institution. Resistance rates of tobramycin and amikacin were relatively stable over this time, while the resistance rates of gentamicin were somewhat more variable. For comparison, we examined resistance rates to piperacillin-tazobactam, cefepime, meropenem, ciprofloxacin, and colistin. Resistance rates to the first four antibiotics were also stable, although uniformly higher for ciprofloxacin. Colistin resistance rates were initially quite low, rose substantially, and then began to decrease at the end of the study. Clinically relevant AME genes were identified in 14% of isolates, and mutations predicted to cause resistance were relatively common in the mexZ and armZ genes. In a regression analysis, resistance to gentamicin was associated with the presence of at least one gentamicin-active AME gene and significant mutations in mexZ, parS, and fusA1. Resistance to tobramycin was associated with the presence of at least one tobramycin-active AME gene. An extensively drug-resistant strain, PS1871, was examined further and found to contain five AME genes, most of which were within clusters of antibiotic resistance genes embedded in transposable elements. These findings demonstrate the relative contributions of aminoglycoside resistance determinants to P. aeruginosa susceptibilities at a United States medical center. IMPORTANCE Pseudomonas aeruginosa is frequently resistant to multiple antibiotics, including aminoglycosides. The rates of resistance to aminoglycosides in bloodstream isolates collected over 2 decades at a United States hospital remained constant, suggesting that antibiotic stewardship programs may be effective in countering an increase in resistance. Mutations in the mexZ, fusA1, parR, pasS, and armZ genes were more common than acquisition of genes encoding aminoglycoside modifying enzymes. The whole-genome sequence of an extensively drug resistant isolate indicates that resistance mechanisms can accumulate in a single strain. Together, these results suggest that aminoglycoside resistance in P. aeruginosa remains problematic and confirm known resistance mechanisms that can be targeted for the development of novel therapeutics.