Antibiotic dosing recommendations in critically ill patients receiving new innovative kidney replacement therapy.

BACKGROUND: The Tablo Hemodialysis System is a new innovative kidney replacement therapy (KRT) providing a range of options for critically ill patients with acute kidney injury. The use of various effluent rate and treatment durations/frequencies may clear antibiotics differently than traditional KRT. This Monte Carlo Simulation (MCS) study was to develop antibiotic doses likely to attain therapeutic targets for various KRT combinations. METHODS: Published body weights and pharmacokinetic parameter estimates were used to predict drug exposure for cefepime, ceftazidime, imipenem, meropenem and piperacillin/tazobactam in virtual critically ill patients receiving five KRT regimens. Standard free ß-lactam plasma concentration time above minimum inhibitory concentration targets (40-60%fT> MIC and 40-60%fT> MICx4) were used as efficacy targets. MCS assessed the probability of target attainment (PTA) and likelihood of toxicity for various antibiotic dosing strategies. The smallest doses attaining PTA ≥ 90% during 1-week of therapy were considered optimal. RESULTS: MCS determined ß-lactam doses achieving ∼90% PTA in all KRT options. KRT characteristics influenced antibiotic dosing. Cefepime and piperacillin/tazobactam regimens designed for rigorous efficacy targets were likely to exceed toxicity thresholds. CONCLUSION: The flexibility offered by new KRT systems can influence ß-lactam antibiotic dosing, but doses can be devised to meet therapeutic targets. Further clinical validations are warranted.

Vancomycin and daptomycin dosing recommendations in patients receiving home hemodialysis using Monte Carlo simulation.

BACKGROUND: Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and differ considerably from conventional, thrice weekly, in-center hemodialysis in terms of treatment frequency, duration and blood and dialysate flow rates. Consequently, vancomycin and daptomycin clearances in HHD are also likely to be different, consequently HHD dosing regimens must be developed to ensure efficacy and minimize toxicity when these antibiotics are used. Many HHD regimens are used clinically, this study modeled ten common HHD regimens and determined optimal vancomycin and daptomycin dosing for each HHD regimen. METHODS: Monte Carlo simulations using pharmacokinetic data derived from the literature and demographic data from a large HHD program treating patients with end stage kidney disease were incorporated into a one-compartment pharmacokinetic model. Virtual vancomycin and daptomycin doses were administered post-HHD and drug exposures were determined in 5,000 virtual patients receiving ten different HHD regimens. Serum concentration monitoring with subsequent dose changes was incorporated into the vancomycin models. Pharmacodynamic target attainment rates were determined for each studied dose. The lowest possible doses that met predefined targets in virtual patients were chosen as optimal doses. RESULTS: HHD frequency, total dialysate volumes and HHD durations influenced drug exposure and led to different dosing regimens to meet targets. Antibiotic dosing regimens were identified that could meet targets for 3- and 7-h HHD regimens occurring every other day or 4-5 days/week. HHD regimens with 3-day interdialytic periods required higher doses prior to the 3-day period. The addition of vancomycin serum concentration monitoring allowed for calculation of necessary dosing changes which increased the number of virtual subjects meeting pharmacodynamic targets. CONCLUSIONS: Doses of vancomycin and daptomycin that will meet desired pharmacodynamic targets in HHD are dependent on patient and HHD-specific factors. Doses used in conventional thrice weekly hemodialysis are unlikely to meet treatment goals. The antibiotic regimens paired with the HHD parameters studied in this analysis are likely to meet goals but require clinical validation.

Comparison of antimicrobial dosing recommendations in patients receiving intermittent hemodialysis among drug information resources.

WHAT IS KNOWN AND OBJECTIVE: Tertiary drug information resources are frequently consulted for the optimal antimicrobial dosing in intermittent hemodialysis (IHD) patients. Yet, significant discrepancy may exist in dosing recommendations between resources. This study was to evaluate the consistency of antimicrobial dosing recommendations in IHD among four different drug information resources and the relevance of referenced pharmacokinetic studies. METHODS: Dosing recommendations of 29 commonly prescribed antimicrobials in IHD patients were collected from Micromedex, LexiComp, Clinical Pharmacology and Drug Prescribing in Renal Impairment to compare dosing categorization and the total daily dose (TDD). Significant dosing discrepancies were defined as ≥30% difference. Referenced pharmacokinetic studies were evaluated for their relevance in current practice, using sample size, hemodialyzer types, the use of optimal pharmacodynamic targets and the consideration of different interdialytic dosing periods. RESULTS AND DISCUSSION: A significant variation was found both in dosing categorization and recommended doses between resources. Seventeen drugs were compared for TDD with significant dosing discrepancy in 8 drugs. Among 42 referenced pharmacokinetic studies, 40 were evaluated. Mean patient numbers of pharmacokinetic studies were 13 ranging from 3 to 70. Sixty per cent of studies utilized contemporary hemodialyzers (e.g., high-flux and/or high efficiency). The optimal pharmacodynamic targets and the impact of different interdialytic intervals were assessed only in 27.5% and 7.5% respectively. WHAT IS NEW AND CONCLUSION: Inconsistent antimicrobial dosing recommendations for IHD patients exist among four well-established resources. Many referenced pharmacokinetic studies utilized outdated or less pharmacodynamically relevant study methods. Newer studies are warranted to reflect contemporary dialysis practice and assess its impact on optimal antimicrobial dosing.

Telavancin pharmacokinetics in patients with chronic kidney disease receiving haemodialysis.

BACKGROUND: Telavancin is a lipoglycopeptide antibiotic with limited pharmacokinetic data to guide drug dosing in patients receiving haemodialysis. OBJECTIVES: This study characterized telavancin pharmacokinetics in patients receiving haemodialysis. PATIENTS AND METHODS: This was a Phase IV, prospective, open-label, single-centre, crossover pharmacokinetic study (ClinicalTrials.gov: NCT02392208). Eight subjects with end-stage kidney disease requiring maintenance haemodialysis (mean ±â€ŠSD: 47 ±â€Š20 years, 69.5 ±â€Š17.1 kg) received 5 mg/kg telavancin IV 3 h before starting a 3.5 hour haemodialysis treatment with a high-permeability haemodialyser (haemodialysis period). After a 14 day washout period, a second 5 mg/kg dose was administered post-haemodialysis (control period). Telavancin plasma concentrations were measured over a 2 day period after each dose and non-compartmental pharmacokinetic analyses were performed. RESULTS: The geometric mean (GM) of telavancin overall clearance was 11.2 mL/h/kg (intrinsic clearance and dialytic clearance) in the haemodialysis period and 5.9 mL/h/kg (off-haemodialysis clearance) in the control period [GM ratio (GMR) = 1.89; 90% CI: 1.70-2.10; P < 0.01]. The GM t½ was 13.1 h when haemodialysis occurred 3 h post-dosing in the haemodialysis period but extended to 20.9 h with post-haemodialysis dosing in the control period (GMR = 0.63; 90% CI: 0.54-0.73; P < 0.01). The GM of telavancin plasma concentrations removed by haemodialysis was 27.7%. The GMR of peak plasma concentration and volume of distribution of the haemodialysis period and the control period were 0.88 (90% CI: 0.79-0.98; P = 0.08) and 1.17 (90% CI: 1.05-1.30; P = 0.048), respectively. CONCLUSIONS: Haemodialysis with high-permeability haemodialysers removes telavancin considerably (∼⅓ of body load). Telavancin 5 mg/kg every 48 h post-haemodialysis dosing is recommended, but dose adjustments may be warranted if haemodialysis starts within 3 h of telavancin administration.

Further Adaptations and Reflections by an Assertive Community Treatment Team to Serve Clients with Severe Mental Illness During COVID-19.

In September of 2020, Guan and colleagues wrote about their experience of an Assertive Community Psychiatry Program responding to the COVID-19 pandemic. We describe our own experience as an Assertive Community Treatment team in Minnesota responding to challenges of effectively and safely delivering service to clients. As the pandemic has progressed since last year, so has the literature, and updated references are highlighted. Common threads are woven between our experience, the experience of Guan and colleagues, and others to suggest the beginnings of a template to adapt services to a new post-pandemic world.

SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis.

Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain-derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage-inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.

A randomized controlled trial of a manual-based psychosocial group intervention for young people with epilepsy [PIE].

We conducted an exploratory RCT to examine feasibility and preliminary efficacy for a manual-based psychosocial group intervention aimed at improving epilepsy knowledge, self-management skills, and quality of life in young people with epilepsy. METHOD: Eighty-three participants (33:50m/f; age range 12-17years) were randomized to either the treatment or control group in seven tertiary paediatric neuroscience centres in the UK, using a wait-list control design. Participants were excluded if they reported suicidal ideation and/or scored above the cut off on mental health screening measures, or if they had a learning disability or other neurological disorder. The intervention consisted of six weekly 2-hour sessions using guided discussion, group exercises and role-plays facilitated by an epilepsy nurse and a clinical psychologist. RESULTS: At three month follow up the treatment group (n=40) was compared with a wait-list control group (n=43) on a range of standardized measures. There was a significant increase in epilepsy knowledge in the treatment group (p=0.02). Participants receiving the intervention were also significantly more confident in speaking to others about their epilepsy (p=0.04). Quality of life measures did not show significant change. Participants reported the greatest value of attending the group was: Learning about their epilepsy (46%); Learning to cope with difficult feelings (29%); and Meeting others with epilepsy (22%). Caregiver and facilitator feedback was positive, and 92% of participants would recommend the group to others. CONCLUSION: This brief psychosocial group intervention was effective in increasing participants' knowledge of epilepsy and improved confidence in discussing their epilepsy with others. We discuss the qualitative feedback, feasibility, strengths and limitations of the PIE trial.

Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy.

BACKGROUND/AIMS: To determine ceftolozane/tazobactam transmembrane clearances (CLTM) in continuous hemofiltration (CHF) and continuous hemodialysis (CHD) and to determine optimal ceftolozane/tazobactam dosing regimens for patients receiving continuous renal replacement therapy (CRRT). METHOD: Validated, ex vivo CHF and CHD bovine blood models using polysulfone (HF1400) and AN69 (Multiflow 150-M) hemofilters were used to evaluate adsorption and CLTM at different effluent flow rates. Monte Carlo simulations (MCS) using pharmacokinetic parameters from published studies and CLTM from this study were used to generate ceftolozane/tazobactam dosing for patients receiving CRRT. RESULTS: CHF and CHD CLTM did not differ at equivalent effluent rates. CLTM approximated effluent flow rates. No adsorption of ceftolozane/tazobactam occurred for either hemofilter. Effluent flow was the most important determinant of MCS-derived doses. CONCLUSION: CRRT clearances of ceftolozane/tazobactam depended on effluent flow rates but not hemofilter types. MCS-derived ceftolozane/tazobactam doses of 750 (500/250)-1,500 (1,000/500) mg every 8 h met pharmacodynamic targets for virtual patients receiving CRRT at contemporary effluent rates.

Antibiotic Dosing in Patients With Acute Kidney Injury: "Enough But Not Too Much".

Increasing evidence suggests that antibiotic dosing in critically ill patients with acute kidney injury (AKI) often does not achieve pharmacodynamic goals, and the continued high mortality rate due to infectious causes appears to confirm these findings. Although there are compelling reasons why clinicians should use more aggressive antibiotic dosing, particularly in patients receiving aggressive renal replacement therapies, concerns for toxicity associated with higher doses are real. The presence of multisystem organ failure and polypharmacy predispose these patients to drug toxicity. This article examines the pharmacokinetic and pharmacodynamic consequences of critical illness, AKI, and renal replacement therapy and describes potential solutions to help clinicians give "enough but not too much" in these very complicated patients.

Exploratory longitudinal cohort study of associations of fatigue after stroke.

BACKGROUND AND PURPOSE: The pathogenesis of poststroke fatigue is unclear. In this prospective study, we explored whether reduced physical activity might contribute to poststroke fatigue or be a consequence of it. METHODS: Patients with a recent acute stroke were assessed at 1, 6, and 12 months with, Fatigue Assessment Scale (FAS), a fatigue case definition, Hospital Anxiety and Depression Score, sleepiness, quality of life, and accelerometry (ActivPAL). Bivariate analyses determined associations between fatigue and step count at each time point. Multiple linear regression tested whether 1-month step count independently predicted 6- and 12-month FAS. RESULTS: A total of 136 participants (mean age, 72 years; 64% men) attended ≥1 assessment. ActivPAL data were available for 84 (64%), 69 (66%), and 58 (64%) participants at 1, 6, and 12 months, respectively. At 6 and 12 months, a positive fatigue case definition was associated with lower daily step counts (P=0.014 and 0.013, respectively). At 1, 6, and 12 months, higher FAS (more fatigue) was associated with lower step count (P<0.001, 0.01, and 0.007), higher depression (P<0.001), anxiety scores (P<0.001) and sleepiness (P<0.001), and poorer quality of life (P<0.001). Lower daily step count (P<0.002 and 0.006) and greater anxiety (P<0.001 for both) at 1 month independently predicted higher FAS at 6 and 12 months. CONCLUSIONS: Lower step counts at 1 month independently predicted greater FAS for ≤12 months. Physical activity might be a therapeutic target for poststroke fatigue.

Tedizolid Adsorption and Transmembrane Clearance during in vitro Continuous Renal Replacement Therapy.

BACKGROUND/AIMS: To study transmembrane clearance (CLTM) and adsorption of tedizolid, a novel oxazolidinone antibiotic, in continuous hemofiltration (CVVH) and continuous hemodialysis (CVVHD). METHODS: In vitro CVVH/CVVHD models with polysulfone and AN69 hemodiafilters were used. Tedizolid CLTM during CVVH/CVVHD was assessed at various ultrafiltrate (Quf) and dialysate rates (Qd). Tedizolid adsorption was tested in a recirculating CVVH model over 4 h. RESULTS: In CVVH, CLTM did not differ between filter types. In CVVHD, tedizolid CLTM was significantly higher with the polysulfone hemodiafilter at Qd 6 l/h (p < 0.02). Tedizolid exhibited irreversible adsorption to the CRRT apparatus and bound significantly higher to the polysulfone hemodiafilter. CONCLUSION: Tedizolid's CLTM is dependent on Qd, Quf, and hemodiafilter type. At conventional CRRT rates, tedizolid CLTM appears modest relative to total body clearance and is unlikely to require dose adjustments. CRRT adsorption in the clinical setting is likely less than what we observed in this in vitro, continuously recirculating blood model.

Antibiotic dosing in critically ill patients receiving CRRT: underdosing is overprevalent.

Published CRRT drug dosing algorithms and other dosing guidelines appear to result in underdosed antibiotics, leading to failure to attain pharmacodynamic targets. High mortality rates persist with inadequate antibiotic therapy as the most important risk factor for death. Reasons for unintended antibiotic underdosing in patients receiving CRRT are many. Underdosing may result from lack of the recognition that better hepatic function in AKI patients yields higher nonrenal antibiotic clearance compared to ESRD patients. Other factors include the variability in body size and fluid composition of patients, the serious consequence of delayed achievement of antibiotic pharmacodynamic targets in septic patients, potential subtherapeutic antibiotic concentrations at the infection site, and the influence of RRT intensity on antibiotic concentrations. Too often, clinicians weigh the benefits of overcautious antibiotic dosing to avoid antibiotic toxicity too heavily against the benefits of rapid attainment of therapeutic antibiotic concentrations in critically ill patients receiving CRRT. We urge clinicians to prescribe antibiotics aggressively for these vulnerable patients.

Stability and compatibility of intraperitoneal antimicrobials in peritoneal dialysate solutions.

To optimise antimicrobial administration in patients with peritoneal dialysis (PD)-related peritonitis, healthcare providers need literature-based information to develop patient-centred pharmacotherapeutic plans. Traditional PD solutions promote osmosis using dextrose or icodextrin with a lactate buffer. Newer PD solutions have modified the osmotic vehicle and buffer. Knowledge of antimicrobial compatibility and stability with newer PD solutions will assist with determining the route of antimicrobial administration as compatible and stable solutions could be delivered directly to the peritoneum using intraperitoneal administration. This review updates the compatibility and stability of antimicrobial additives in newer PD solutions for PD-related peritonitis.

Erratum to "Impact of pharmacist intervention to deprescribe inappropriate aspirin therapy in an outpatient anticoagulation clinic at a community hospital" [Am. Heart J. Plus: Cardiol. Res. Pract. volume 17, May 2022, 100165].

[This corrects the article DOI: 10.1016/j.ahjo.2022.100165.].

IRB perspectives on the return of individual results from genomic research.

PURPOSE: Return of individual research results from genomic studies is a hotly debated ethical issue in genomic research. However, the perspective of key stakeholders-institutional review board (IRB) professionals-has been missing from this dialogue. This study explores the positions and experiences of IRB members and staff regarding this issue. METHODS: In-depth interviews with 31 IRB professionals at six sites across the United States. RESULTS: IRB professionals agreed that research results should be returned to research participants when results are medically actionable but only if the participants want to know the results. Many respondents expected researchers to address the issue of return of results (ROR) in the IRB application and informed-consent document. Many respondents were not comfortable with their expertise in genomics research and only a few described actual experiences in addressing ROR. Although participants agreed that guidelines would be helpful, most were reticent to develop them in isolation. Even where IRB guidance exists (e.g., Clinical Laboratory Improvement Act (CLIA) lab certification required for return), in practice, the guidance has been overruled to allow ROR (e.g., no CLIA lab performs the assay). CONCLUSION: An IRB-researcher partnership is needed to help inform responsible and feasible institutional approaches to returning research results.

Genetics researchers' and IRB professionals' attitudes toward genetic research review: a comparative analysis.

PURPOSE: Genetic research involving human participants can pose challenging questions related to ethical and regulatory standards for research oversight. However, few empirical studies describe how genetic researchers and institutional review board (IRB) professionals conceptualize ethical issues in genetic research or where common ground might exist. METHODS: Parallel online surveys collected information from human genetic researchers (n = 351) and IRB professionals (n = 208) regarding their views about human participant oversight for genetic protocols. RESULTS: A range of opinions were observed within groups on most issues. In both groups, a minority thought it likely that people would be harmed by participation in genetic research or identified from coded genetic data. A majority of both groups agreed that reconsent should be required for four of the six scenarios presented. Statistically significant differences were observed between groups on some issues, with more genetic researcher respondents trusting the confidentiality of coded data, fewer expecting harms from reidentification, and fewer considering reconsent necessary in certain scenarios. CONCLUSION: The range of views observed within and between IRB and genetic researcher groups highlights the complexity and unsettled nature of many ethical issues in genome research. Our findings also identify areas where researcher and IRB views diverge and areas of common ground.

The use of pedometers in stroke survivors: are they feasible and how well do they detect steps?

OBJECTIVES: To determine (1) the feasibility of pedometers for stroke patients and (2) the level of agreement between pedometers and actual step count. DESIGN: Observational agreement study. SETTING: Six stroke units. PARTICIPANTS: Independently mobile stroke patients (N=50) ready for hospital discharge. INTERVENTIONS: Patients were asked to apply 3 pedometers: 1 around the neck and 1 above each hip. Patients performed a short walk lasting 20 seconds, then a 6-minute walk test 6MWT. Video recordings determined the criterion standard step count. MAIN OUTCOME MEASURE: Agreement between the step count recorded by pedometers and the step count recorded by viewing the criterion standard video recordings of the 2 walks. RESULTS: Five patients (10%) needed assistance to put on the pedometers, and 5 (10%) could not read the step count. Thirty-nine (78%) would use pedometers again. Below a gait speed of about 0.5 m/s, pedometers did not generally detect steps. Agreement analyses showed that even above 0.5 m/s, pedometers undercounted steps for both the short walk and 6MWT; for example, the mean difference between the video recorder and pedometer around the neck was 5.93 steps during the short walk and 32.4 steps during the 6MWT. CONCLUSIONS: Pedometers are feasible but generally do not detect steps at gait speeds below about 0.5 m/s, and they undercount steps at gait speeds above 0.5 m/s.

Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers.

Aberrant glycosylation is a pathological alteration that is widespread in colon cancer, and usually accompanies the onset and progression of the disease. To date, the molecular mechanisms underlying aberrant glycosylation remain largely unknown. In this study, we identify somatic and germ-line mutations in the gene encoding for polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12) in individuals with colon cancer. Biochemical analyses demonstrate that each of the 8 GALNT12 mutations identified inactivates the normal function of the GALNT enzyme in initiating mucin type O-linked protein glycosylation. Two of these inactivating GALNT12 mutations were identified as acquired somatic mutations in a set of 30 microsatellite stable colon tumors. Relative to background gene mutation rates, finding these somatic GALNT12 mutations was statistically significant at P < 0.001. Six additional inactivating GALNT12 mutations were detected as germ-line changes carried by patients with colon cancer; however, no inactivating variants were detected among cancer-free controls (P = 0.005). Notably, in 3 of the 6 individuals harboring inactivating germ-line GALNT12 mutations, both a colon cancer and a second independent epithelial cancer had developed. These findings suggest that genetic defects in the O-glycosylation pathway in part underlie aberrant glycosylation in colon cancers, and they contribute to the development of a subset of these malignancies.

An optimal extended-infusion dosing of cefepime and ceftazidime in critically ill patients with continuous renal replacement therapy.

PURPOSE: This study aimed to determine optimal extended-infusion dosing regimens for cefepime and ceftazidime in critically ill patients receiving continuous renal replacement therapy using Monte Carlo Simulations (MCS). MATERIALS AND METHODS: Pharmacokinetic models were built using published pharmacokinetic/demographic data to predict drug disposition in 5000 virtual critically ill patients receiving continuous venovenous hemofiltration (CVVH) with the standard (20-30 mL/kg/h) and a higher (40 mL/kg/h) effluent rates. MCS was performed to assess the probability of target attainment (PTA) of four cefepime and ceftazidime doses administered over 4-h with the target of ≥60% fT > 4×MIC. The lowest dose attaining PTA ≥90% during the first 48-h was considered optimal. Additionally, risk of drug toxicity was assessed at 48-h using suggested neurotoxicity thresholds. RESULTS: Cefepime 2 g loading dose (LD), then extended-infusion of 2 g q8hr was optimal in CVVH at 20 mL/kg/h and the same ceftazidime dose was optimal in CVVH at 20-30 mL/kg/h. Higher cefepime and ceftazidime doses were required to be optimal at higher effluent rates. This optimal dose particularly for cefepime likely increases neurotoxicity risk in most virtual patients with all CVVH settings. CONCLUSIONS: Cefepime and ceftazidime 2 g LD, followed by extended-infusion 2 g q8hr may be optimal in CVVH with standard effluent rates.