24-hour Infusion Research Articles

Cefepime extended infusion versus intermittent infusion: Clinical and cost evaluation.

Extended infusion cefepime (1 gram every 6 hours administered over 3 hours) achieves pharmacodynamic efficacy against bacteria with a MIC of ≤8 mg/L in Monte Carlo simulations. This regimen has not been evaluated in clinical practice. Compare clinical and economic outcomes for cefepime by intermittent infusion and by extended infusion in the acute-care setting. Single-center, retrospective cohort study. Tertiary-care academic medical center. Hospitalized adults who received cefepime between August 2016 and July 2018 with a diagnosis of sepsis or pneumonia. Clinical and economic outcomes were compared for patients who received empiric cefepime via intermittent infusion (30-minute infusion of 2 g every 8 hours) or extended infusion (3-hour infusion of 1 g every 6 hours). Clinical outcomes analyses were carried out using appropriate statistical methods. Overall, 111 patients received intermittent infusion and 93 patients received extended infusion. Approximately half of the included patients had a positive culture for a bacterial pathogen (intermittent infusion 45.9% vs extended infusion 47.3%). Median hospital length of stay (intermittent infusion 6 days vs extended infusion 6 days; P = .67) and 90-day readmission rates (intermittent infusion 61.3% vs extended infusion 67.7%; P = .34) did not differ between the groups. Mortality was infrequent in both groups (intermittent infusion 2.9% vs extended infusion 1.5%; P = .45). Cefepime cost per patient was lower with cefepime by extended infusion: average total daily cost $86.06 for intermittent infusion versus $43.39 for extended infusion. Cefepime via extended infusion (4 grams/day) did not differ in clinical outcomes compared to intermittent infusion (6 grams/day) but reduced drug expenditure. Prospective, multicenter, high-quality studies should be conducted to evaluate a mortality difference between these regimens.

Piperacillin/Tazobactam Dose Optimization in the Setting of Piperacillin/Tazobactam-susceptible, Carbapenem-resistant Pseudomonas aeruginosa: Time to Reconsider Susceptible Dose Dependent

This study evaluates the in vitro potency of piperacillin/tazobactam among a global collection of carbapenem-resistant Pseudomonas aeruginosa (CR-PA) and assesses the adequacy of the Clinical and Laboratory Standards Institute (CLSI) P aeruginosa breakpoint dose in the setting of CR-PA using Monte Carlo simulation. Isolates were collected during the Enhancing Rational Antimicrobials Against Carbapenem-Resistant P aeruginosa (ERACE-PA) Global Surveillance Program. Piperacillin/tazobactam MICs were determined using broth microdilution per CLSI standards. A 5000-patient Monte Carlo simulation was performed using various piperacillin/tazobactam dosing regimens to determine the probability of target attainment (PTA) for 50% free time above the MIC. The MIC distribution of piperacillin/tazobactam-susceptible CR-PA was used to calculate cumulative fraction of response (CFR). Optimal PTA and CFR were defined as 90% target achievement. A total of 28% of tested CR-PA were piperacillin/tazobactam susceptible. Of these, 71% had MICs of 8 to 16/4 mg/L. Doses of 3.375 g q6h as 0.5-hour infusion (current breakpoint dose) had adequate PTA at MIC of 8/4 mg/L (CFR, 81%); however, extended infusion of 3 or 4 hours improved PTA at 16/4 mg/L (CFR, >90%). Doses of 4.5 g q8h as a 4-hour infusion and 4.5 g q6h as a 3-hour infusion both provide >90% PTA at an MIC of 16 mg/L (CFRs, 97 and 100%, respectively), favoring susceptible dose dependent interpretive criteria with these regimens. Although susceptible, piperacillin/ tazobactam has reduced potency in CR-PA. If piperacillin/tazobactam is used for susceptible CR-PA, high-doses (4.5 g q6h) and extended infusion (3 hours or continuous infusion) are needed to optimize exposure.

615. Pharmacodynamics (PD) of the Beta-Lactamase Inhibitor Xeruborbactam When Administered in Combination with Meropenem

Abstract Background Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. The purpose of these studies was to determine the pharmacodynamic parameter that best described the activity of XERU against Enterobacterales and A. baumannii when administered in combination with a fixed dosage regimen of meropenem in the neutropenic mouse thigh infection model. 24h Free Xeruborbactam AUC vs CRE 24h Free Xeruborbactam AUC vs CRAB Methods Seven carbapenem resistant Enterobacterales (CRE) and six carbapenem-resistant A. baumannii (CRAB) isolates were used in these studies. Mice were rendered neutropenic, infected with ∼107 CFU/thigh and were treated with various doses of XERU in combination with meropenem (300 mg/kg q2h) by the IP route starting 2 hours post infection for 24 hours. The meropenem dosage regimen was fixed and designed to simulate 2 g every 8 hours by 3-hour infusion in humans. Plasma exposures (PK) were measured in neutropenic, infected mice. The relationship between XERU PK-PD indices and the reduction in the log number of CFU per thigh were analyzed by using the sigmoid Emax PD model. Results The activity of XERU was best described by the % 24h free XERU plasma concentrations exceeded 1 mg/L and 24h free xeru plasma AUC. Xeru PK-PD Parameters in Combination with Meropenem against CRE Xeru PK-PD Parameters in Combination with Meropenem against CRAB Conclusion The PK-PD of XERU was best described by the % 24h free XERU plasma concentrations exceeded 1 mg/L and 24h free XERU plasma AUC. The PK-PD of XERU in combination with meropenem and the clinical PK of both drugs support further clinical development for the treatment of carbapenem-resistant isolates of Enterobacterales and A. baumannii. Disclosures Ziad Tarazi, Qpex Biopharma: Employee Niki Roos, n/a, Qpex Biopharma: Employee Ted Page, n/a, Qpex Biopharma: Employee David Griffith, n/a, Qpex Biopharma: Employee.

624. Probability of Target Attainment of Ceftolozane/Tazobactam Among Adult Patients with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia Secondary to Pseudomonas aeruginosa in Latin America

Abstract Background Pseudomonas aeruginosa (Pa) is a common cause of nosocomial pneumonia; resistance among traditionally used empiric agents is observed frequently. To improve patient outcomes, a heightened focus has been placed on evaluating the adequacy of recommended dosing regimens, particularly of beta-lactams. The Phase 3 study ASPECT-NP demonstrated the efficacy and safety of 3 g of ceftolozane/tazobactam (C/T) infused every 8 h for 8 to 14 days for treatment of adults with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia (HAP/VAP). We assessed the Probability of Target Attainment (PTA) of the C/T 3g dosage regimen in patients with HAP/VAP due to Pa, with an additional focus on carbapenem-resistant Pa, from Latin America. Methods Non duplicate Pa isolates from a respiratory source were collected as part of the SMART surveillance program from 36 sites in 10 Latin American countries during 2017-2020. MICs were determined by broth microdilution and interpreted by CLSI criteria. C and T concentration-time profiles were simulated in plasma and ELF following administration of the approved 3g (2g/1g) C/T dose (or equivalent dose adjusted based on renal function) administered by 1-hour infusion every 8 hours. PTA in plasma and ELF was calculated using the PK/PD target of 30% fT > MIC for C. T does not contribute to the antipseudomonal activity of C and therefore was not considered. Results A total of 2,757 P. aeruginosa were collected, of which 1208 (43.8%) were carbapenem nonsusceptible. C/T susceptiblity was 87.7% against all Pa and 73.4% among carbapenem nonsusceptible strains. At C/T doses of 2g/1g (CrCL > 50mL/min); 1g/0.5g (30mL/min≤ CrCL≤ 50mL/min), and 500mg/250mg (15mL/min≤ CrCL≤29mL/min), steady-state ceftolozane plasma and ELF PTA was 100% and > 99%, respectively, for isolates with an MIC at the Pa susceptiblity breakpoint of 4 µg/mL. Ceftolozane plasma and ELF PTA remained above 90% up to an MIC of 16 µg/mL and 8 µg/mL, respectively. Conclusion The regulatory approved pneumonia dosage regimen of C/T 3g (administered over 1 hour) every 8 hours (or equivalent dose adjusted based on renal function) resulted in high plasma and ELF PTAs sufficient to cover the vast majority of circulating P. aeruginosa present in Latin America, including carbapenem resistant strains. Disclosures Aline Okuma, PharmD, MSD Brazil: Employee Thales Polis, MD, MSD Brazil: Employee Jacqueline Pavia, MD, MSD COLOMBIA: EMPLOYEE Gustavo Mizuno, PharmD, MSD Brazil: Employee Jacqueline Ferrari, MD, MSD Brazil: Employee Charles A. DeRyke, PharmD, Merck & Co., Inc. Merck Research Laboratories: Stocks/Bonds.

654. Clinical efficacy and safety of high dose Ampicillin sulbactam among patients with CRAB infections: A case series

Abstract Background CRAB continues to threaten the healthcare facilities in developing nations and is one among the commonest causes of hospital acquired infections in our hospital. In December 2021, the IDSA published the AMR guidance 2.0, that stated Ampicillin- sulbactam as the first choice for treating CRAB infections. We review the clinical outcomes with adherence to this guideline in our setting. Methods A descriptive study from India (January 2022 to April 2022), of in-patients who have received ampicillin sulbactam monotherapy or combination for CRAB infections. A standard treatment guideline for the identification and management of CRAB infections was introduced to the clinicians based on the AMR guidance 2.0 of IDSA. CRAB infections were classified as mild to severe based on clinical and radiological parameters. We collected the data on patients who were started on ampicillin sulbactam, given in a high dose (27g per day or renally adjusted) as a 4-hour infusion either alone or as combination with other antibiotics for the indication of CRAB infections. Results Ampicillin-Sulbactam was started for 12 patients with CRAB infection. 2 of these patients were discharged while on treatment and hence, excluded. 6 out of the 10 patients were being treated for CRAB associated hospital acquired pneumonia, whereas the other indications included urinary tract infection, post neurosurgical meningitis and skin and soft tissue infections. Susceptibility testing to Ampicillin-Sulbactum was not possible in our setting. All the patients survived from 14 days of starting the therapy and 9 out of 10 patients improved clinically (in terms of defervescence or symptomatic relief) by day 7. No adverse effects were noted either in clinical symptoms or Laboratory parameters during the course of treatment. Conclusion High dose Ampicillin-Sulbactum is effective and safe for CRAB infections with varying clinical syndromes and severity. All patients in this case series were treated with Colistin sparing regimens when combination therapy was required. Disclosures All Authors: No reported disclosures.

Liposomal Amphotericin-B Infusion-related Reactions and Rate of Infusions: A Single Center Cohort Study

Objectives: Liposomal amphotericin B is a broad-spectrum antifungal treatment used for life-threatening infections, but it commonly induces infusion-related adverse events that may prevent treatment completion. Based on anecdotal evidence, a slow infusion guideline at treatment initiation has been suggested to reduce these reactions. This study aimed to determine if slowing down the infusion rate on treatment initiation would reduce the rate of infusion-related adverse events.
 Methods: A retrospective cohort study was conducted examining the primary outcome of adverse event rates between patients who received slow and standard (2-hour or faster) infusions at a major hospital in Australia. Secondary outcomes were risk factors associated with infusion reactions. The rates of adverse events were analyzed using Fisher’s exact test.
 Results: An 8-year audit identified 47 patients who were administered liposomal amphotericin-B. The average age of the study population was 61.7 years and 28 (59.6%) were male patients. Slower than standard infusions were given to 5 (10.6%) patients on treatment initiation. Infusion-related adverse events occurred in 2 (40.0%) patients with reduced rates and 5 (11.9%) patients with standard infusion rates (p=0.154). Typical reactions were myalgia, dyspnoea, and flushing. Four patients with adverse events had been rechallenged after further rate reductions and prophylactic medications with the completion of treatment. No risk factors for adverse events were identified among demographics, comorbidities, or co-prescribed medications.
 Conclusion: Slowing the infusion rate of liposomal amphotericin-B administration does not appear to reduce the likelihood of infusion-related reactions, however, it can be trialed for adverse-event management. J Microbiol Infect Dis 2022; 12(4): 148-153.

Outpatient Administration of High-Dose Methotrexate for Leukemia and Lymphoma in Adults without Drug Monitoring: Risk Factors for Acute Kidney Injury

Introduction: Methotrexate is an antifolate that has been an essential part of regimens for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), when it is used in high-dose (HD, ≥ 1 g/m2) to overcome the blood-brain barrier. Nephrotoxicity is the major toxicity of HDMTX, inducing critical organ damage and death if not early detected and treated. Therefore, these regimens are usually administered in the hospital, with intravenous (IV) hydration, drug level, urine pH monitoring, and MTX-guided leucovorin rescue. Although some factors for drug-induced acute kidney injury (AKI) have been pointed and recommendations are published, the reality is that in resource-poor settings, HDMTX is usually administered in an outpatient clinic and without drug monitoring. The exact incidence of AKI after MTX in these conditions was not reported in adults yet. In this study, we intend to summarize our toxicity data after outpatient administration of HDMTX without drug monitoring. We aim to find risk factors and describe their outcomes. Methods This is a retrospective nested case-control study conducted at an academic medical center in Sao Paulo, Brazil. Patients from 16 years old and above with ALL and NHL who received at least one outpatient infusion of HDMTX without drug level monitoring between Jan/2010 and Jun/2020 were included. Most patients with ALL received a 6-hour infusion, while those with NHL received a 2-hour infusion in a day clinic, along with intravenous hydration, urine alkalinization, and leucovorin rescue. Patients were followed outpatient by a multidisciplinary team. Cases were those patients who developed AKI by KDIGO definition or with delayed MTX clearance (serum MTX level > 0.1 mM after 72h from drug infusion), when clinically suspected. A nested cohort of controls was composed of patients who did not develop the complication, sampling from a larger cohort of patients who received HDMTX. Cases and controls were randomly matched 1:2 for the employed protocol only. Hematologic and liver toxicity were graduated according to CTCAE v5.0. Conditional logistic regression was used to find baseline risk factors. Results A total of 404 patients received at least one HDMTX infusion, with 102 not fulfilling the inclusion criteria. Among 302 patients included, 840 infusions were performed (median 2 infusions/patient, range 1-10). Most patients had a diffuse large B-cell lymphoma (DLBCL) (37%), Burkitt lymphoma (BL) (19.5%), or ALL (18%) diagnosis, followed by other NHL subtypes (25.5%). Most subjects received HDMTX within a course of Hyper-CVAD (HCVAD) or monotherapy (61%). Hospitalization occurred in 8.6% of infusions during the MTX nadir, with 4.6% needing intensive care, being febrile neutropenia the most common complication (63%). Twenty-five patients presented AKI after HDMTX administration, corresponding to 3% (95% CI 2-4.4) of MTX infusions and 8.3% (95% CI 5.5-12.1) of patients. Characteristics of cases are summarized in Table 1. Univariate analysis for finding pre-treatment factors related to AKI after HDMTX were age>44 y (OR 3.2 [95% CI 1 - 9.7], p=0.045), body surface≥1.76 m2 (OR 3.4 [95% CI 1.2-9.9], p=0.039), BMI≥23.8 kg/m2 (OR 3.5 [95% CI 1.2-9.9], p=0.02), baseline creatinine clearance (OR 0.96 [95% CI 0.93-0.99], p=0.012), thrombocytopenia (<150x109/L) (OR 4.7 [95% CI 1.7-13.1], p=0.002). Multivariate analysis for adjusting such factors found that only BMI is independently related to AKI after HDMTX in our setting (OR 3.8 [95% CI 1.2-11.8], see figure 1). Among those patients with AKI, 9/25 had their MTX serum level measured at the AKI, with delayed MTX clearance in 7/9. HIV-associated BL was more frequent in cases (18 vs. 6.8%, p=0.03). Concerning remaining toxicities, grade 3 or more thrombocytopenia, neutropenia, and hyperbilirubinemia were found in 36%, 64%, and 36%, respectively. 22/25 needed hospitalization, with infection diagnosed in 23/25 e need for dialysis in 5/25 cases. Death after AKI occurred in 56% (14/25). Conclusions Our data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fare worse than expected, with more hospitalizations and death. Higher BMI was associated with MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CTNI-36. INITIATION OF A PHASE 1 DOSE-ESCALATING STUDY OF WEEKLY DIRECT-TO-BRAIN ADMINISTRATION OF SOLUBILISED FORMULATION OF PANOBINOSTAT (MTX110) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (MAGIC-G1 STUDY)

Abstract INTRODUCTION Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, leading to universal recurrence despite aggressive surgical and chemotherapeutic treatment. Post-recurrence, median overall survival is 6 to 10 months and treatment options are very limited. One of the biggest challenges in treating GBM is achieving high local drug concentration; systemic administration of cytotoxic agents has failed in the past due to this limitation. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming this challenge. MTX110 (Midatech Pharma Ltd) is a water-soluble form of panobinostat, that demonstrated cytotoxic activity in 4 GBM cell lines (U87MG, U251MG, U118MG and T98G) with an average IC50 value around 40nM which also translated into pre clinical in vivo efficacy, in combination with radiotherapy1. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumour, thus avoiding systemic administration and therefore toxicity. This has previously been demonstrated in investigator-initiated studies of paediatric patients with diffuse intrinsic pontine glioma. METHOD MAGIC-G1 study is a Phase 1 two-cohort dose-escalating study that will assess safety and feasibility of intermittent intratumoral administration of MTX110 by CED to rGBM patients; either as a single agent (Cohort 1) or in combination with lomustine (Cohort 2). Eligible patients will have a catheter system and an abdominal refillable pump implanted in an aseptic manner, with the tip of the catheter positioned stereotactically at the centre of the tumour. 48-hour infusions will be administered weekly until disease progression and doses of 30, 60 and 90 mM will be investigated. Cohort 1 recruitment will be completed before Cohort 2 starts dosing. Study results are expected in 2023.

Safety, Tolerability, and Pharmacokinetics of Intravenous Doses of PF-07304814, a Phosphate Prodrug Protease Inhibitor for the Treatment of SARS-CoV-2, in Healthy Adult Participants.

Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. PF-07304814 (lufotrelvir) is the phosphate prodrug of PF-00835231, a protease inhibitor targeting the 3C-like protease of SARS-CoV-2. This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single ascending intravenous doses of lufotrelvir (continuous 24-hour infusion of 50, 150, 500, or 700 mg) versus placebo in healthy volunteers (2 interleaving cohorts: 1, n = 8; 2, n = 7). Each dosing period was separated by a washout interval (≥5 days). Treatment-emergent adverse events, PK, and biomarker concentrations were estimated from plasma/urine samples. Lufotrelvir was administered to 15 volunteers (mean [SD] age 39.7 [11.8] years). No serious adverse events, discontinuations, or deaths were reported. Mean maximum observed concentration of PF-00835231 (active moiety; 97.0 ng/mL to 1288 ng/mL) were observed between median time to maximum concentration of 14 to 16 hours after the start of the lufotrelvir infusion. Near-maximum plasma concentrations of PF-00835231 were observed ≈6 hours after infusion start and sustained until infusion end. PF-00835231 plasma concentrations declined rapidly after infusion end (mean terminal half-life: 500 mg, 2.0 hours; 700 mg, 1.7 hours). Approximately 9%-11% of the dose was recovered in urine as PF-00835231 across doses. A continuous, single-dose, 24-hour infusion of lufotrelvir (50-700 mg) was rapidly converted to PF-00835231 (active moiety), with dose-proportional PK exposures and no significant safety concerns. A daily, 24-hour continuous infusion of 270 to 350 mg is expected to maintain PF-00835231 concentration at steady state/above effective antiviral concentrations. Further studies exploring lufotrelvir efficacy in patients with coronavirus disease 2019 are ongoing.

ASSESSMENT OF EFFICIENCY OF ALPHA-LIPOIC ACID AND IPIDACRINE HYDROCHLORIDE TREATMENT FOR PREVENTION OF PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY USING THE EQ-5D 5L QUALITY OF LIFE QUESTIONNAIRE

Introduction. Paclitaxel is the most common chemotherapeutic agent from the taxane family, which is effective in treating many cancer types, including breast cancer. Despite the benefits of taxane-containing treatment regimens, patients develop neurosensory and neuromotor symptoms associated with the treatment, a condition known as chemotherapy-induced peripheral neuropathy.&#x0D; The aim of the study. To evaluate the efficacy of a combination of alpha-lipoic acid and acetylcholinesterase inhibitor ipidacrine hydrochloride to prevent the development of paclitaxel-induced peripheral neuropathy and improve its course in patients with breast cancer using the data of the EQ-5D 5L Quality of Life Questionnaire.&#x0D; Materials and methods. The study was conducted on 70 patients with breast cancer (T1-4N0-3M0-1), who were hospitalized at the Precarpathian Clinical Oncology Center of Ivano-Frankivsk Regional Council in 2014-2022. All patients received six cycles of chemotherapy according to the AT or ET regimens: paclitaxel at a dose of 175 mg/m2 as a 3-hour infusion + doxorubicin 60 mg/m2 (AT), or paclitaxel at a similar dose + epirubicin 90 mg/m2 (ET) once in 3 weeks in neoadjuvant, adjuvant or palliative modes. Patients were randomized into two groups: patients of group I (n = 35) received polychemotherapy without the use of drugs for the prevention of neuropathy, and patients of group II (n = 35) received polychemotherapy and a preventive treatment of neuropathy. The scheme for the prevention of paclitaxel-induced peripheral neuropathy included a combination of alpha-lipoic acid with an acetylcholinesterase inhibitor ipidacrine hydrochloride. In order to assess the quality of life and effectiveness of the studied paclitaxel-induced peripheral neuropathy prevention regimen in patients with breast cancer, we have used the EQ-5D 5L quality of life questionnaire before and after the 3rd and 6th cycles of paclitaxel chemotherapy.&#x0D; Results. The study of breast cancer patients showed a statistically significant deterioration in all five aspects of quality of life included in the EQ-5D 5L quality of life questionnaire, which progressed with increasing cumulative dose of paclitaxel. In addition, the application of the study scheme for the prevention of paclitaxel-induced peripheral neuropathy in patients of group II, in contrast to patients of group I, led to a statistically significant improvement according to their answers to questions about pain or discomfort, both after 3 and after 6 cycles of chemotherapy with paclitaxel - by 14.09 % (p &lt; 0.05) and 19.49 % (p &lt; 0.01), respectively. According to the questionnaire data, after 6 cycles of chemotherapy self-care of patients of group II in contrast to patients of group I significantly improved (by 21.21 %, p &lt; 0.05). Patients' answers to questions about the other three aspects of quality of life (mobility, normal daily activities, anxiety or depression) did not show a significant improvement in patients of group II, both after 3 and 6 cycles of paclitaxel chemotherapy. The mean value of the assessment of the general condition according to the visual-analog scale significantly improved after 3 and 6 cycles of chemotherapy with paclitaxel in patients of group II, in contrast to patients of group I - by 6.80 % (p &lt; 0.001) and 13.40 % (p &lt; 0.001), respectively.

Pharmacokinetics/Pharmacodynamics and tolerability of cefiderocol in the clinical setting.

Cefiderocol is a new cephalosporin with a catechol in its chemical structure faciliting its access to the interior of bacteria through iron channels. In addition, it is broadly stable to beta-lactamases. The pharmacokinetic profile is a beta-lactam one: no oral absorption, and with a wide distribution within the vascular space and the interstitial fluid of well vascularized tissues, reaching therapeutic concentrations in the alveolar lavage fluid and within the macrophage. The binding of cefiderocol to human plasma proteins, primarily albumin, is moderate (range 40-60%). The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. Cefiderocol is mainly renally eliminated, so dose adjustments are recommended in subjects with moderate / severe renal impairment, in case of dialysis, and probably in patients with external clearance. Like other beta-lactams, the PK / PD parameter that has been shown to best correlate with efficacy is the efficacy time of unbound plasma concentrations (%fT>MIC), which must be close to 100% to achieve a bactericidal effect. This is possible with 2 g in a 3-hour infusion every 8 hours. In controlled trials appears to be well tolerated, similar to comparators: meropenem or imipenem-cilastatin. Cefiderocol has no apparent clinically significant effect on ECG parameters nor on plasma iron values.

Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis

Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections. To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis. A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens. Eligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline). The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified. Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events. Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis. ClinicalTrials.gov Identifier: NCT03687255.

Biapenem: Clinical and Microbiological Characteristics and the Place of The New Carbapenem In The Treatment of Severe Infections In The Hospital. Clinical Pharmacologists' Point of View

A new carbapenem antibiotic — biapenem — previously used only in Japan and Southeast Asia, was registered in Russia in 2021. The article analyzes the antimicrobial, pharmacokinetic, and clinical characteristics of biapenem in detail, provides pharmacodynamic justifications for antibiotic dosing. The most important properties and advantages of biapenem related to antimicrobial action (higher activity and eradication potential against Pseudomonas aeruginosa), the highest stability among carbapenems to carbapenemases of classes D (OXA-48-type) and B (NDM-type) are emphasized, which determines a new option for the treatment of infections caused by carbapenem-resistant Enterobacterales (biapenem in combination with polymyxin/colistin and/or tigecycline). Among the features of pharmacokinetics, it is necessary to highlight low albumin binding (3.7%), good tissue penetration, as well as stable pharmacokinetics of biapenem in patients in critical condition, septic shock, and those requiring renal replacement therapy. Pharmacodynamic modeling has established the most optimal dosage of biapenem in sepsis and septic shock: 300 mg (3-hour infusion) every 6 hours or 600 mg every 12 hours. A dosage regimen of 300 mg QID is preferable in patients undergoing continuous renal replacement therapy. The effectiveness of biapenem has been documented in numerous studies, which also show good antibiotic tolerability and safety: the frequency of side effects averaged 2% and was lower than that of other carbapenems. Biapenem can be effectively and safely prescribed to the most problematic elderly patients with serious comorbid conditions and impaired kidney and liver function.

Treatment Outcome and Safety of the TCX Regimen for Advanced Gastric Cancer: A Prospective Cohort Study.

ObjectiveTo evaluate the outcome and safety of the paclitaxel, carboplatin, and capecitabine (TCX) regimen in patients with advanced gastric cancer.MethodsAdvanced gastric cancer patients received the TCX regimen for up to six cycles, which were 3 weeks apart. Paclitaxel (175 mg/m2) was given over a 3-hour infusion, followed by carboplatin in a 1-hour infusion on day 1. Capecitabine (850 mg/m2) was given orally twice daily from day 1 to day 14. Primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsAmong 83 patients at stage IVa and IVb, the median PFS was 9.3 months; 6-month, 1-year, and 2-year PFS were 74.6%, 32.5%, and 14.4%, respectively. The median OS was 17.0 months; 6-month, 1-year, and 2-year OS were 97.5%, 68.7%, and 21.7%, respectively. In the multivariable Cox regression model, higher CEA was associated with poor OS. Common adverse events included hand-food syndrome (77.9%), peripheral neuropathy (63.2%), fatigue (68.7%), and nausea (54.2%).ConclusionThe TCX regimen provided good survival and a better safety profile. More clinical trials are needed to confirm its treatment efficacy and safety, especially in comparison with other triplet regimens.

Compatibility and stability of an admixture of multiple anaesthetic drugs for opioid-free anaesthesia.

The ability to combine and use drugs in a single infusion device may be useful in resource-limited settings. This study examined the chemical stability of an opioid-sparing mixture of ketamine, lidocaine and magnesium sulphate when combined in a single syringe. High-performance liquid chromatography and atomic absorption spectrophotometry were performed on six syringes containing the three-drug mixture. Since most opioid-sparing techniques typically rely on a 24-hour infusion regime, we tested stability at the initial admixing and 24 hours later. Stability was defined as a measured drug concentration within 10% of expected, with the absence of precipitation or pH alterations. Pharmacokinetic simulations were conducted to further show that the achieved plasma drug concentrations were well within an effective analgesic range. All mixed drug concentration measurements were within the required 10% reference limit. No obvious precipitation or interaction occurred, and pH remained stable. Drug stability was maintained for 24 hours. Pharmacokinetic simulations showed that ketamine and lidocaine were within their minimum analgesic effect concentrations. Our results show that this three-drug mixture is chemically stable for up to 24 hours after mixing, with a pharmacokinetic simulation illustrating safe, clinically useful predicted plasma concentrations when using the described admixture.

Bilateral Ultrasound-Guided Erector Spinae Plane Block for Pectus Excavatum Surgery: A Retrospective Propensity-Score Study

Pectus excavatum (PE) repair is burdened by severe postoperative pain. This retrospective study aimed to determine whether the analgesic effect of ultrasound-guided erector spinae plane block (ESPB) plus standard intravenous analgesia (SIVA) might be superior to SIVA alone in pain control after PE surgical repair via Ravitch or Nuss technique. A retrospective cohort study. At a university hospital. All participants were scheduled for surgical repair of PE. From January 2017 to December 2019, all patients who received ESPB plus SIVA or SIVA alone were investigated retrospectively. A 2:1 propensity-score matching analysis considering preoperative variables was used to compare analgesia efficacy in 2 groups. All patients received a 24-hour continuous infusion of tramadol, 0.1 mg/kg/h, and ketorolac, 0.05 mg/kg/h, via elastomeric pump, and morphine, 2 mg, intravenously as a rescue drug. The ESPB group received preoperative bilateral ESPB block. Postoperative pain, reported using a numerical rating scale at 1, 12, 24, and 48 hours after surgery; the number of required rescue doses; total postoperative morphine milligram equivalents consumption; and the incidence of postoperative nausea and vomit were analyzed. A total of 105 patients were identified for analysis. Propensity-score matching resulted in 38 patients in the SIVA group and 19 patients in the ESPB group. Postoperative pain, the number of rescue doses, and postoperative nausea and vomit incidences were lower in the ESPB group (p < 0.005). Erector spinae plane block may be an effective option for pain management after surgical repair of PE as part of a multimodal approach. This study showed good perioperative analgesia, opioid sparing, and reduced opioid-related adverse effects.

Induction chemotherapy regimen of docetaxel plus cisplatin versus docetaxel, cisplatin plus fluorouracil followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: Preliminary results of an open-label, noninferiority, multicentre, randomised, controlled phase 3 trial.

SummaryBackgroundInduction chemotherapy regimens of docetaxel and cisplatin plus fluorouracil (TPF) are currently clinically used for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) but have well-known side effects, such as myelosuppression and diarrhea. A docetaxel plus cisplatin (TP) regimen was developed to decrease the toxic effects induced by fluorouracil. In this trial, we assessed whether the TP induction chemotherapy regimen was noninferior to the TPF regimen.MethodsWe performed an open-label, noninferiority, phase 3, multicentre, randomised, controlled trial at six centres in China. Eligible patients with NPC (stage III-IVA (excluding T3-4N0), Karnofsky's Performance Scoring ≥70) were randomly assigned (1:1) to receive either TP (docetaxel (75 mg per square meter, d1, intravenous infusion) and cisplatin (75 mg per square meter of body-surface area, d1, intravenous infusion)) or TPF (docetaxel (60 mg per square meter, d1, intravenous infusion) plus cisplatin (60 mg per square meter, d1, intravenous infusion) and 5-fluorouracil (600 mg per square meter, d1-d5, intravenous 120-hour infusion)) administered every 3 weeks for 3 cycles followed by concurrent chemoradiotherapy. The primary endpoint was failure-free survival at 2 years. Secondary endpoints included overall survival, safety, and treatment compliance. The trial was stopped early because of strong evidence for noninferiority (margin was -10%) of TP in failure-free survival. Efficacy analyses were performed in both the intention-to-treat and per-protocol trial populations and we included the patients who started treatment in each group for the safety analysis. The study was registered with chictr.org.cn, ChiCTR1800016337.FindingsBetween June 1, 2018 and October 31, 2021, we randomly assigned 361 patients to the TP (n = 181) or TPF (n = 180) induction chemotherapy group. The 2-year failure-free survival was 91·3% (95% CI 86·2-96·4) in the TP group and 82·4% (84·8-88·9) in the TPF group (P = 0·029). Patients in the TPF group had a higher frequency of grade 1 or 2 neutropenia (53 (30·0%) vs. 28 (15·7%); P = 0·0010), grade 1 or 2 diarrhea (20 (11·3%) vs. 9 (5·1%); P = 0·032), and grade 3 or 4 neutropenia (43 (24·3%) vs. 25 (14·0%); P = 0·014) in the induction chemotherapy period. There was no treatment-related death.InterpretationThe preliminary results revealed that TP induction chemotherapy regimen was found to be clearly non-inferior compared to the TPF regimen in failure-free survival, with a lower frequency of neutropenia, anaemia and diarrhoea. The more convenient and beneficial survival regimen of the TP regimen should be recommended in patients with LA-NPC.FundingThis study was supported by grants from the Natural Science Foundation of Guangdong Province, China [grant number 2021A1515011182], Natural Science Foundation of Guangdong Province, China [grant number 2022A1515012272], National Natural Science Foundation of China [grant number 82072029] and National Natural Science Foundation of China [grant number 81903037].

Water intake, thirst, and copeptin responses to two dehydrating stimuli in lean men and men with obesity.

Physiological systems responsible for water homeostasis and energy metabolism are interconnected. This study hypothesized altered responses to dehydration including thirst, ad libitum water intake, and copeptin in men with obesity. Forty-two men (22 lean and 20 with obesity) were stimulated by a 2-hour hypertonic saline infusion and a 24-hour water deprivation. In each dehydrating condition, thirst, ad libitum water intake after dehydration, and urinary and hormonal responses including copeptin were assessed. After each dehydration condition, ad libitum water intake was similar between both groups (p > 0.05); however, those with obesity reported feeling less thirsty (p < 0.05) and had decreased copeptin response and higher urinary sodium concentrations when stressed (p < 0.05). Angiotensin II, aldosterone, atrial and brain natriuretic peptides, and apelin concentrations did not differ by adiposity group and did not explain the different thirst or copeptin responses in men with obesity. However, leptin was associated with copeptin response in lean individuals during the hypertonic saline infusion (p < 0.05), but the relationship was diminished in those with obesity. Diminished thirst and copeptin responses are part of the obesity phenotype and may be influenced by leptin. Adiposity may impact pathways regulating thirst and vasopressin release, warranting further investigation.

Population-Based Pharmacokinetics and Dose Optimization of Imipenem in Vietnamese Critically-Ill Patients.

PurposeThe purpose of this study was to characterize the population-based pharmacokinetic (POP-PK) profile of imipenem in Vietnamese adult patients and to assess the probability of target attainment (PTA) of the pharmacokinetic/pharmacodynamic (PK/PD) parameter to determine the optimal dose.Patients and MethodsA POP-PK model of imipenem was developed in patients with severe infection from a 1500-bed general hospital in Vietnam, using MONOLIX 2019. After the initial dose infusion, 6 blood samples per patient were collected to measure plasma imipenem levels. Eight covariates (eg, age, weight) were investigated to ascertain their influence on imipenem’s PK. Monte Carlo simulations were performed to determine the PTA for the time in which the total steady-state imipenem concentrations remained above the MIC (T>MIC) for 40% and 100% of the dosing interval.ResultsThe best fit to the PK data was a two-compartment model with inter-individual variability (IIV) in clearance (CL), central volume of distribution (Vc), intercompartmental clearance (Q), and peripheral volume of distribution (Vp). Only creatinine clearance was retained as a covariate on CL in the final model. The typical value of CL and Vc were estimated to be 4.79 L/h and 11.1 L, respectively. The between-subject variability in this population was noted to be high (>38%, especially for IIV on Q at 110%). Prolonged or continuous infusion demonstrated efficacy (40% T>MIC) against bacteria with a MIC of 4mg/L. To achieve 100% T>MIC or bacteria with MIC>4 mg/L, however, the number of doses must be increased while maintaining the same daily dose for the 3-hour prolonged infusion regimen.ConclusionA population pharmacokinetic model of imipenem was developed for Vietnamese adult patients with severe illness. By using Monte Carlo simulation, the appropriate dose has been suggested based on the bacterial MIC value and the targeted PK/PD goal.

Uncovering Discrepancies in IV Vancomycin Infusion Records between Pump Logs and EHR Documentation.

Infusion start time, completion time, and interruptions are the key data points needed in both area under the concentration-time curve (AUC)- and trough-based vancomycin therapeutic drug monitoring (TDM). However, little is known about the accuracy of documented times of drug infusions compared with automated recorded events in the infusion pump system. A traditional approach of direct observations of infusion practice is resource intensive and impractical to scale. We need a new methodology to leverage the infusion pump event logs to understand the prevalence of timestamp discrepancies as documented in the electronic health records (EHRs). We aimed to analyze timestamp discrepancies between EHR documentation (the information used for clinical decision making) and pump event logs (actual administration process) for vancomycin treatment as it may lead to suboptimal data used for therapeutic decisions. We used process mining to study the conformance between pump event logs and EHR data for a single hospital in the United States from July to December 2016. An algorithm was developed to link records belonging to the same infusions. We analyzed discrepancies in infusion start time, completion time, and interruptions. Of the 1,858 infusions, 19.1% had infusion start time discrepancy more than ± 10 minutes. Of the 487 infusion interruptions, 2.5% lasted for more than 20 minutes before the infusion resumed. 24.2% (312 of 1,287) of 1-hour infusions and 32% (114 of 359) of 2-hour infusions had over 10-minute completion time discrepancy. We believe those discrepancies are inherent part of the current EHR documentation process commonly found in hospitals, not unique to the care facility under study. We demonstrated pump event logs and EHR data can be utilized to study time discrepancies in infusion administration at scale. Such discrepancy should be further investigated at different hospitals to address the prevalence of the problem and improvement effort.