Dosing Strategies Research Articles

Optimizing Individualized Antimicrobial Dosing in Pediatric Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Therapeutic drug monitoring (TDM) and target concentration intervention (TCI) represent significant advancements in individualized medicine, aiming to tailor dosages based on patient-specific characteristics. These approaches account for intra- and inter-individual physiological and clinical variability, with the goal of improving target attainment and clinical remission while reducing treatment failure and adverse effects. The objective is to assess and enhance the current body of randomized controlled trials (RCTs) that have investigated alternative personalized dosing strategies, such as TDM and TCI, in terms of their efficacy and safety for individualized antimicrobial dosing in pediatric populations. Only studies that compared different dosing regimens and reported plasma concentrations were included in the analysis. Databases such as MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until January 3rd, 2024. Only published, peer-reviewed RCTs were considered for inclusion. The study focused on human subjects aged < 18 years who were receiving an antimicrobial drug. The interventions compared experimental dosing versus standard dosing with TDM or TCI. The risk of bias was assessed using version 2 of the Cochrane risk-of-bias tool for randomized trials. The primary outcome was the attainment of target concentrations, while secondary outcomes included adverse effects, clinical remission, and treatment failure. Data synthesis was performed using the restricted maximum likelihood method, and the risk ratio (RR) was used as the measure of effect size. Only 11 TDM-based RCTs were included in the study [experimental vs standard doses: 592 (51.3%) patients vs 563 (48.7%) patients]. Experimental dose was significantly associated with improvement in target attainment (RR 1.2587, OR 1.0717-1.4786; p=0.0051). However, experimental antimicrobial dose optimization was non-significantly associated with a numerical decrease in treatment failure (RR 0.8966, OR 0.7749-1.0374; p=0.1424). In addition, it was not significant associated with higher adverse effects [RR 1.3408, odds ratio (OR) 0.1783-10.0825; p=0.7757] and clinical remission rates (RR 4.0589, OR 0.2494-66.0558; p=0.3250). This meta-analysis showed that only target attainment using TDM was significantly improved in pediatric patients treated with experimental doses of antimicrobials compared to standard doses. Larger TCI-focused RCTs are needed to significantly improve treatment failure, adverse effects, and clinical remission.

Evaluation of Response to Weight-based Dosing Strategies of Continuous, Fixed-Rate Atracurium Infusions in Critically Ill, Obese Adults With Acute Respiratory Distress Syndrome.

Fixed-rate infusions of weight-based neuromuscular blocking agents (NMBAs) were adopted during the COVID pandemic to limit caregiver exposure during titrations. Although fixed-rate infusions are supported in studies of acute respiratory distress syndrome (ARDS), the optimal scalar for weight-based NMBAs in patients with obesity remains controversial. This study sought to compare change in oxygenation using two weight-based dosing strategies for atracurium in obese patients with ARDS. Secondary outcomes included total atracurium dose, mortality, and intensive care unit (ICU) and ventilator-free days. Following an institutional practice update to use ideal body weight (IBW) for patients with obesity, we retrospectively compared adults (≥18 years) with ARDS and a body mass index (BMI) ≥ 30 kg/m2 who received atracurium (15 µg/kg/min) based on actual body weight (ABW) with those using IBW. The primary outcome was change in PaO2/FiO2 ratio (P/F) 48 hours after atracurium initiation. Analysis-of-covariance compared change in P/F between groups after adjustment for confounders. The IBW group (n = 123), compared with the ABW group (n = 133), had lower baseline P/F (85.0 [71.0, 118.3] vs 93.3 [76.0, 128.3], P = 0.025) and sequential organ failure assessment (SOFA) score (9.7 ± 2.6 vs 10.5 ± 2.6, P = 0.015), with greater use of steroids (96% vs 89%, P = 0.032) and prone positioning (72% vs 58%, P = 0.015). No difference was detected in change in P/F at 48 hours (adjusted least squares mean [95% confidence interval, CI]: 55.8 [37.0, 74.5] vs 56.9 [39.6, 74.1], P = 0.90). Atracurium doses were higher in the ABW group (97.4 mg/h [84.4, 110.3] vs 55.4 [47.2, 65.7], P < 0.001). There was no difference in hospital mortality, ICU mortality, and ICU-free days or ventilator-free days. In patients with obesity with ARDS receiving fixed-rate atracurium infusions, the change in P/F at 48 hours did not differ based on weight. Atracurium dosed on IBW may use less total drug without compromising ability to improve oxygenation. This is the first study comparing the dosing weight used for continuous infusion atracurium in hospitalized, critically ill ARDS patients with obesity. Additional studies are warranted to optimize dosing in obese patients.

Comment on: Toward an optimal contraception dosing strategy.

The optimal contraception dosing strategy proposed by Gavina et al. recently is a commendable attempt to model a complex physiological process with potenial to apply to real-life data. However, there is a need to take into account the real challenges that arise when moving from the theory to its practical application, and it is important that lessons learnt from clinical studies be taken into consideration in any theoretical modelling. In this manuscript, we spell out these lessons and elaborate practical challenges facing their model.

The Beneficial Roles of Seaweed in Atopic Dermatitis

Atopic dermatitis (AD) is a chronic, inflammatory skin condition characterized by severe pruritus and recurrent flare-ups, significantly impacting patients’ quality of life. Current treatments, such as corticosteroids and immunomodulators, often provide symptomatic relief but can lead to adverse effects with prolonged use. Seaweed, a sustainable and nutrient-dense resource, has emerged as a promising alternative due to its rich bioactive compounds—polysaccharides, phlorotannins, polyphenols, and chlorophyll—that offer anti-inflammatory, antioxidant, and immunomodulatory properties. This review explores the therapeutic potential of brown, red, and green algae in alleviating AD symptoms, highlighting the effects of specific species, including Undaria pinnatifida, Laminaria japonica, Chlorella vulgaris, and Sargassum horneri. These seaweeds modulate immune responses, reduce epidermal thickness, and restore skin barrier function, presenting a novel, safe, and effective approach to AD management. Further clinical studies are needed to confirm their efficacy and establish dosing strategies, paving the way for seaweed-derived therapies as natural alternatives in AD treatment.

Reassessing Ivabradine: Potential Benefits and Risks in Atrial Fibrillation Therapy.

Ivabradine has been identified as a funny current (If) inhibitor in the sinoatrial node (SAN) and is considered an advocated therapeutic agent in chronic heart failure and stable angina. This therapeutic agent has shown positive benefits in maintaining a reduction in heart rate while sustaining hemodynamic stability. Its clinical application is still evolving and the mechanism of action is becoming clearer daily. The use of this agent to manage atrial fibrillation (AF) has recently been brought under discussion. This study summarizes the mechanism of action of ivabradine and current evidence about the risk of new-onset AF and rate-lowering potential as a therapeutic option in patients suffering from AF. This review synthesizes findings from preclinical studies, case reports, and clinical trials that assess ivabradine's efficacy in controlling heart rate and its association with new-onset AF. Studies have shown that this medication may be beneficial in ventricular rate reduction in patients intolerant of first-line AF therapeutic options, including non-dihydropyridine calcium channel blockers and β-blockers. However, it is important to state that ivabradine-treated patients with cardiovascular diseases demonstrated an increased risk for new-onset AF compared with those patients who did not receive it. While ivabradine demonstrates promise as a therapeutic option for rate control in patients with AF, its use is accompanied by a notable risk of new-onset AF. Further studies should focus on optimal dosing strategies and long-term outcomes of ivabradine treatment in AF management.

Nutrient conditions affect antimicrobial pharmacodynamics in Pseudomonas aeruginosa.

The infectious microenvironment in chronic respiratory tract infections is characterized by substantial variability in nutrient conditions, which may impact colonization and treatment response of pathogens. Metabolic adaptation of the cystic fibrosis (CF)-associated pathogen Pseudomonas aeruginosa has been shown to lead to changes in antibiotic sensitivity. The impact of specific nutrients on the response to antibiotics is, however, poorly characterized. Here, we investigated how different carbon sources impact the antimicrobial pharmacodynamic responses in P. aeruginosa. We evaluated the effect of six antibiotics (aztreonam, ceftazidime, ciprofloxacin, colistin, imipenem, and tobramycin) on P. aeruginosa cultured in a basal medium enriched for seven different carbon sources (alanine, arginine, aspartate, glucose, glutamate, lactate, and proline). Pharmacodynamic responses were characterized by measuring time-kill profiles for a bioluminescent P. aeruginosa PAO1 Xen41 strain. We show that single-nutrient modifications minimally affected bacterial growth rate. For specific nutrient-antibiotic combinations, we find relevant alterations in antibiotic sensitivity (i.e., EC50) and the maximum drug effect (Emax), in particular for ciprofloxacin, colistin, imipenem, and tobramycin. The most pronounced effect was observed for tobramycin, where glucose was found to reduce the EC50 (0.5-fold), whereas lactate-enriched conditions led to a 4.3-fold increase in EC50. Using pharmacokinetic-pharmacodynamic simulations, we illustrate that the magnitude of the nutrient-driven pharmacodynamic changes impact treatment for clinical dosing strategies of tobramycin. In summary, this study underscores the impact of nutrient composition on antimicrobial pharmacodynamics, which could potentially contribute to observed variability of antimicrobial treatment responses in CF patients.IMPORTANCEChronic respiratory tract infections in cystic fibrosis patients present significant challenges for antibiotic treatment due to the complexity of the respiratory environment. This study investigated how variations in nutrient levels, altered during chronic infections, affect pathogen response to antibiotics in an experimental setting. By simulating different nutrient conditions, we aimed to uncover interactions between nutrient availability and antibiotic sensitivity. Our findings provide critical insights that could lead to more effective treatment strategies for managing chronic respiratory tract infections in cystic fibrosis patients while also guiding future research in improving treatment methodologies.

Time to Loss of Disease Control Following Guselkumab Withdrawal in Relation to Initial Speed of Response: A Post-Hoc Analysis of the VOYAGE 2 Trial

Background: Psoriasis is a chronic inflammatory skin disorder typically requiring lifelong treatment. As such, patients may occasionally need treatment breaks. Understanding factors predicting maintenance of disease control during treatment breaks could improve long-term disease management. This post-hoc analysis of data from the Phase 3 VOYAGE 2 clinical trial evaluates how initial speed of response to guselkumab treatment affects time to loss of disease control following treatment withdrawal and identifies baseline characteristics corresponding with maintenance of disease control. Methods: Patients with moderate-to-severe plaque psoriasis assigned to treatment withdrawal following achievement of a Psoriasis Area and Severity Index (PASI)90 response after two or four guselkumab doses. Loss of disease control was defined as time to PASI ≥3 and was assessed using Kaplan–Meier analysis. The relationship between baseline characteristics and maintenance of response was evaluated using a Cox proportional hazards model. Results: Of patients who were randomized to placebo and switched to guselkumab at Week 16, 149/248 (60%) achieved PASI90 after two guselkumab doses (Week 28). Of patients who were randomized to guselkumab, 377/496 (76%) achieved PASI90 after four guselkumab doses (Week 28), of whom 182 were then re-randomized to withdrawal. Of these, 131 had achieved PASI90 after two guselkumab doses (Week 12) and 51 had achieved PASI90 after four guselkumab doses (Week 28). Maintenance of disease control following guselkumab withdrawal was longer in patients who achieved PASI90 after two versus four guselkumab doses. Lower body mass index, biologic naïve status, and shorter disease duration at baseline corresponded with a longer time to PASI ≥3 following withdrawal. Conclusion: Faster initial response to guselkumab resulted in longer maintenance of disease control after treatment withdrawal. These findings may be used to inform personalized dosing strategies with guselkumab, which may increase patient compliance to treatment and improve long-term treatment outcomes.

Evaluation of the Efficacy of Piperacillin/Tazobactam in Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae Urinary Tract Infections: A Systematic Review of the Literature.

To evaluate the efficacy of piperacillin/tazobactam (PTZ) for the treatment of extended-spectrum beta-lactamase-producing enterobacteriaceae (ESBL-PE) urinary tract infections (UTIs). A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards on PubMed, MEDLINE, Embase, Web of Science Core Collection, and Cochrane Central through July 2024. Studies providing efficacy data associated with PTZ in patients ≥18 years old experiencing an ESBL-PE UTI that documented clinical and microbiological cure data were included. A total of 577 articles were obtained for screening. After applying the inclusion and exclusion criteria, 7 studies comparing PTZ with carbapenems comprised of 1156 patient cases were analyzed. Piperacillin/tazobactam was found to be noninferior to carbapenems in the treatment of both uncomplicated and complicated UTI's caused by ESBL-PE. The observed noninferiority encompassed clinical response, clinical cure, and microbiological cure outcome metrics. Although not specifically evaluated in this systematic review, adverse effects associated with PTZ were found to be minimal and lesser in incidence than with the carbapenem comparators in aggregate. While a definitive dosing strategy remains elusive, a PTZ total daily dose of 13.5 g infused over 3 to 4 hours may be appropriate for this indication. Piperacillin/tazobactam may be an effective carbapenem-sparing agent for the treatment of ESBL-PE UTIs that show in-vitro susceptibility to PTZ. However, additional robust randomized clinical trials are still needed to validate the findings of this review and determine the best dosage regimen of PTZ for ESBL-PE UTIs.

Anidulafungin exposure and population pharmacokinetics in critically ill patients with invasive candidiasis.

Anidulafungin is recommended as a first-line treatment for invasive Candida infections in critically ill patients. Pharmacokinetic (PK) variability is large in critically ill patients, potentially compromising pharmacokinetic-pharmacodynamic (PKPD) target attainment under standard dosing. We aimed to assess anidulafungin exposure, PKPD target attainment, and population (pop)PK in critically ill patients. Adult ICU patients receiving standard anidulafungin dosing [200mg on day 1, then 100mg daily] were included (NCT04045366). We performed rich blood sampling on an early (day 2 ± 1) and/or late (day 5 ± 1) treatment day. Using total anidulafungin plasma concentrations, we developed a popPK model (NONMEM7.5) and conducted Monte Carlo simulations (n = 1,000 per virtual patient) to evaluate the impact of patient factors on PKPD target attainment (AUC24h target 83.5mg×h/L). Twenty patients contributed 188 anidulafungin concentrations. PKPD target attainment was 45% and 65% on early and late sampling days, respectively. A two-compartment popPK model with first-order elimination described the data. Anidulafungin clearance increased with bodyweight and central volume of distribution increased as serum albumin decreased. Both bodyweight and serum albumin had a clinically relevant impact on PKPD target attainment at day 1 (area under the ROC curve; AUROC 0.82 and 0.62, respectively), and bodyweight on PKPD target attainment at day 14 (AUROC 0.94). Standard anidulafungin dosing regimen fails to achieve adequate target attainment throughout the treatment period. Standard anidulafungin dosing is insufficient for achieving adequate exposure in critically ill patients. An interactive simulation tool is provided to aid dose-finding research and explore different dosing strategies and targets.

Semi-mechanistic population pharmacokinetic modeling of DZIF-10c, a neutralizing antibody against SARS-Cov-2: predicting systemic and lung exposure following inhaled and intravenous administration

DZIF-10c (BI 767551) is a recombinant human monoclonal antibody of the IgG1 kappa isotype. It acts as a SARS-CoV-2 neutralizing antibody. DZIF-10c has been developed for both systemic exposure by intravenous infusion as well as for specific exposure to the respiratory tract by application as an inhaled aerosol generated by a nebulizer. An integrated preclinical/clinical semi-mechanistic population pharmacokinetic model was developed to characterize the exposure profile of DZIF-10c in the systemic circulation and lungs. To inform and reduce uncertainty around exposure in the lungs following different methods of dosing, preclinical cynomolgus monkey data was combined with human data using allometric scaling principles. Human serum concentrations of DZIF-10c from two clinical trials were combined with serum/plasma and lung epithelial lining fluid (ELF) concentrations from three preclinical studies to characterize the relationship between dosing, serum/plasma, and lung exposure. The final model was used to predict exposure in the lungs following different routes of administration. Simulations showed that inhalation provides immediate and relevant exposure in the lung ELF at a much lower dose compared with an infusion. Combining inhalation with intravenous therapy results in high and sustained DZIF-10c exposure in the lungs and systemic circulation, thereby combining the benefits of both routes of administration. By combining preclinical data with clinical data (via allometric scaling principles), the developed population pharmacokinetic model reduced uncertainty around exposure in the lungs allowing evaluation of alternative dosing strategies to achieve the desired concentrations of DZIF-10c in human lungs.

SON-1010: an albumin-binding IL-12 fusion protein that improves cytokine half-life, targets tumors, and enhances therapeutic efficacy.

Cytokines have been promising cancer immunotherapeutics for decades, yet only two are licensed to date. Interleukin-12 (IL-12) is a potent regulator of cell-mediated immunity that activates NK cells and interferon-γ (IFNγ) production. It plays a central role in multiple pathways that can enhance cancer cell death and modify the tumor microenvironment (TME). Attempts to dose rIL-12 were initially successful but IFNγ toxicity in Phase 2 complicated further development in the late 1990s. Since then, better dosing strategies have been developed, but none have achieved the level of cancer control seen in preclinical models. We set out to develop a novel strategy to deliver fully functional IL-12 and other biologics to the TME by binding albumin, taking advantage of its ability to be concentrated and retained in the tumor. Single-chain variable fragments (scFv) were identified from a human phage display library that bound human, mouse, and cynomolgus macaque serum albumin, both at physiologic and acidic conditions. These were taken through a series of steps to identify strongly binding molecules that don't interfere with the normal physiology of albumin to bind FcRn, giving it prolonged half-life in serum, along with SPARC/GP60, which allows albumin to target the TME. A final molecule was chosen and a single mutation was made that minimizes the potential for immunogenicity. This fully human albumin-binding (FHAB®) domain was characterized and manufacturing processes were developed to bring the first drug candidate into the clinic. Once identified, the murine form of mIL12-FHAB was studied preclinically to understand its mechanism of action and biodistribution. It was found to be much more efficient at blocking tumor growth compared to murine IL-12, while stimulating significant IFNγ production with minimal toxicity. SON-1010, which uses the human IL-12 sequence, passed through all of the characterization and required toxicology and is currently being studied in the clinic. We identified and developed a platform technology with prolonged half-life that can target IL-12 and other immune modulators to the TME. Safety and efficacy are being studied using SON-1010 as monotherapy and in combination with checkpoint blockade strategies.

Evaluation of unfractionated heparin therapy for venous thromboembolism using adjusted body weight in elderly or higher weight patients.

The use of weight-based unfractionated heparin (UFH) infusions is the standard of care in hospital management of venous thromboembolism (VTE). Initial dosing strategies for UFH in older adults and higher body weight patients remain uncertain given differences in pharmacokinetics and concerns for over-anticoagulation. Methods: This was a single-center, retrospective, pre-post study involving older adults aged ≥ 65years and patients weighing ≥ 100kg with suspected or confirmed VTE to determine if the use of adjusted body weight (AdjBW)-based UFH regimens improves time to therapeutic anti-Xa levels compared to total body weight (TBW)-based regimens Patients received weight-based UFH infusions, dosed according to either TBW or AdjBW, to target a therapeutic anti-Xa level. Each cohort consisted of 40 patients, stratified by whether they met age or weight criteria to ensure equal representation of elderly and higher body weight patients between cohorts. The median time to therapeutic anti-Xa levels was shorter in the AdjBW group compared to the TBW group (13.6h versus 20.9h; point estimate 5.3h (95% CI 0.2 to 9.9)). This finding was driven by those aged ≥ 65years and those who received a bolus dose at the start of the infusion. Among older adults and higher weight adults with suspected or confirmed VTE, the use of AdjBW to guide heparin infusion initiation was associated with shorter time to therapeutic anti-Xa levels. This finding driven by the older adult sample and the subgroup analyses did not find a statistically significant difference in time to therapeutic anti-Xa levels in higher body weight patients aged less than 65years.

Assessing population-based to personalized planning strategies for head and neck adaptive radiotherapy.

Optimal head-and-neck cancer (HNC) treatment planning requires accurate and feasible planning goals to meet dosimetric constraints and generate robust online adaptive treatment plans. A new x-ray-based adaptive radiotherapy (ART) treatment planning system (TPS) version 2.0 emulator includes novel methods to drive the planning process including the revised intelligent optimization engine algorithm (IOE2). HNC is among the most challenging and complex sites and heavily depends on planner skill and experience to successfully generate a reference plan. Therefore, we evaluate the new TPS performance via conventionally accepted planning strategies with/without artificial intelligence (AI) and knowledge-based planning (KBP). Our institution has a pre-clinical release of the Varian Ethos2.0 TPS emulator which includes several changes that may affect current planning strategies. Twenty definitive and post-operative HNC patients were retrospectively selected with a two or three-level simultaneous integrated boost (SIB) dosing scheme. Patients were replanned in the emulator using population-based, KBP-guided with/without human intervention and AI-guided planning goals. These planning strategies were compared both dosimetrically and for plan deliverability. All strategies generally demonstrated acceptable plan quality with KBP- and AI-guided goals offering enhanced dosimetric sparing in organs-at-risk (OAR). The average contralateral parotid gland mean dose was 20.0±6.1Gy (p<0.001) for population-based and 15.0±6.1Gy (p=n.s.) for KBP-with human intervention versus 15.1±7.4Gy for clinical plans. Target coverage, minimum dose, and plan hotspot were acceptable in all cases. KBP-enabled strategy demonstrated higher modulation and faster optimization time than both population-based and AI-guided strategies. Simply entering population, automatic KBP-enabled or AI-generated planning goals into the new Ethos2.0 TPS produced dosimetrically compliant plans, with AI-guided goals demonstrating the most OAR sparing. Several of these approaches are easy to translate to other treatment sites and will help lower the barrier to entry for x-ray-based online-ART.

Clinical outcomes of a twice daily metronidazole dosing strategy for Bacteroides bloodstream infections.

The optimal metronidazole dose for the treatment of Bacteroides spp. has not been well-defined. This study was a multicenter, retrospective chart review of adult patients with bacteremia secondary to Bacteroides spp. between October 2010 and March 2024. Clinical outcomes of patients who received 500mg of metronidazole twice daily were compared to those who received 500mg of metronidazole thrice daily. Clinical failure defined as a composite of 30-day recurrent infection due to Bacteroides spp. or all-cause mortality. Of the 242 patients who met the inclusion criteria, 76 received metronidazole 500mg twice daily and 166 received metronidazole 500mg thrice daily. Patients who received metronidazole twice daily did not have significantly different rates of clinical failure (15% vs 18%, P=0.561) or 30-day mortality (15% vs 17%, P=0.638) compared to those who received metronidazole thrice daily. After applying full-cohort matching, patients who received metronidazole twice daily were not at an increased risk of clinical failure [OR=0.859; 95% CI (0.283-2.606); P= 0.801] or 30-day mortality [OR = 0.897, 95% CI (0.292-2.752) P=0.8573]. In the largest study to date of patients with Bacteroides spp. bacteremia treated with metronidazole, twice daily dosing strategies were not associated with worse outcomes compared to thrice daily metronidazole dosing strategies.

Assessing Practice Patterns Regarding Use of Norethindrone Acetate in Adolescents.

Norethindrone acetate (NETA) is commonly used in adolescent patients for management of heavy menstrual bleeding, menstrual suppression, and endometriosis. Clinical guidelines do not address specific dosing strategies, clinical indications, contraindications, or monitoring. We sought to survey current prescribers of NETA to assess practice patterns of use among adolescent patients. An anonymous cross-sectional survey was sent via email list-serv to members of the North American Society for Pediatric and Adolescent Gynecology Providers (NASPAG). Participants were asked about their own demographics, patterns of use and monitoring of NETA. Seventy-one providers participated in the survey including 46 gynecologists and 22 adolescent medicine trained clinicians. The most common indications for use were menstrual suppression and treatment of endometriosis. Most providers (n=51) used NETA in patients with estrogen contraindications, with over half limiting the maximum dose used (n=24). While 14%(n=9) of providers surveyed had concerns about effects on bone mineral density with prolonged NETA use, only 1 participant routinely obtained dual-energy X-ray absorptiometry (DEXA) scans. 43% of participants using NETA felt there were no absolute contraindications (n=27); others cited liver disease (n=15), active or prior venous thromboembolism (n=7), and inherited thrombophilia or increased clotting risk (n=3) as strict contraindications. NETA is commonly prescribed for adolescents by study participants. Despite widespread use, practice patterns vary regarding eligibility, monitoring, and perceived risks. This likely reflects limited data and highlights the need for further investigations of NETA use. Our study was limited by low response rate that may not be reflective of general clinical practice.

Sulfur powder utilization and denitrification efficiency in an elemental sulfur-based membrane bioreactor with coagulant addition

The integration of elemental sulfur-based autotrophic denitrification with membrane bioreactor (MBR) technology offers a cost-effective solution for nitrate removal; however, stable operation demands efficient sulfur utilization and phosphorus management. This study explores sulfur consumption dynamics and the impacts of coagulant injection on denitrification efficiency. Sulfur consumption was closely correlated with nitrate removal rates, highlighting the critical role of stoichiometric sulfur availability for sustained denitrification. While coagulant addition enhanced phosphorus removal, excessive dosing impaired elemental sulfur-based microbial activity, reducing nitrate removal efficiency and increasing nitrite accumulation. Notably, microbial community analysis revealed a decline in the abundance of key sulfur-oxidizing bacteria, such as Sulfurimonas, under high coagulant concentrations. These findings emphasize the need for optimized sulfur and coagulant dosing strategies to balance phosphorus and nitrate removal while preserving microbial diversity and reactor stability. This study provides practical insights into operational parameters for efficient and sustainable ESAD-MBR processes.

Pharmacokinetic/pharmacodynamic analysis of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults by Monte Carlo simulation

The objective of this study was to investigate the cumulative fraction of response of various dosage regimens of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults. Monte Carlo simulations (MCSs) were performed using previously published pharmacokinetic parameters and pharmacodynamic data to evaluate the efficacy of the simulated dosage strategies in terms of area under the concentration-time curve/minimum inhibitory concentration targets of tedizolid. According to the results of the MCSs, currently approved dosage regimens of tedizolid phosphate were effective in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) including vancomycin intermediate, heterogeneous vancomycin intermediate, and daptomycin-non-susceptible MRSA in adult and pediatric patients aged 12 years and older. However, high-dose regimens of tedizolid phosphate should be the preferred option to optimize efficacy against ABSSSIs caused by linezolid-resistant MRSA, particularly cfr-mediated isolates. Furthermore, the dosage regimens of 3 and 4 mg/kg/day of tedizolid phosphate were appropriate to treat ABSSSIs caused by MSSA and MRSA in children aged 2 to 6 and 6 to 12 years, respectively. Moreover, approved dosage regimens of tedizolid phosphate for patients older than 12 years may be sufficient against Streptococcus pneumoniae pneumonia but insufficient for Staphylococcus aureus pneumonia. For neutropenic patients, almost all the simulated regimens of tedizolid phosphate were ineffective against Staphylococcus aureus and Streptococcus pneumoniae. These pharmacokinetics/pharmacodynamics-based simulations rationalize and optimize the dosage regimens of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults.

Pharmacokinetic Modeling and Model-Based Hypothesis Generation for Dose Optimization of Clonidine in Neonates With Neonatal Opioid Withdrawal Syndrome.

The No-POPPY study (NCT03396588), a double-blind, randomized trial compared morphine with clonidine therapy for neonatal opioid withdrawal syndrome (NOWS) and found that the duration of treatment was similar across groups. This is significant because perinatal use of morphine has the potential for neurodevelopmental consequences. Still, the clonidine group reached symptom stabilization (Finnegan score (FS) < 8) later than the morphine group and had a more significant number of patients who required adjunct therapy. However, the mean FS was consistently lower in the clonidine group after day 6. This prompted us to use pharmacokinetic (PK) and parametric time-to-event (TTE) modeling to simulate dosage schedules that may decrease the time to stabilization and reduce the need for adjunct therapy. Population PK (popPK) analysis was conducted, and the final model was a one-compartment model with first-order absorption and elimination, incorporating allometric scaling and age effect on apparent clearance (CL/F) and apparent volume (V/F). The population estimates for CL/F and V/F were 13.6 L/h/70 kg and 416 L/70 kg, respectively, similar to the reported values. A Weibull model described the TTE data best, followed by incorporating predicted average concentrations to yield the final Weibull accelerated failure time model. Simulations of dosing strategies showed that increasing both the starting and maximum doses could potentially shorten the time to stabilization, and thus, length of treatment and hospital stay. Given the hypothesis-generating nature of this analysis, the recommended dosing regimens should be tested prospectively to evaluate their benefits.

Significant haematological alterations in clozapine-treated patients: prevalence and clinical correlation.

Clozapine is an atypical antipsychotic crucial for treatment-resistant schizophrenia, characterised by its multi-receptor targeting, including serotonin (5-HT2A, 5-HT2C) and dopamine (D1, D2, D3, D4) receptors, among others. This broad mechanism is effective against positive symptoms of schizophrenia with a lower incidence of extrapyramidal side effects. However, clozapine poses significant haematological risks, notably agranulocytosis, necessitating stringent blood monitoring protocols. This study examined haematological parameters in 157 patients on clozapine therapy, analysing the prevalence and clinical correlations of haematological abnormalities such as leucocytosis, thrombocytosis, and alterations in red blood cell distribution width (RDW) and mean platelet volume (MPV). The findings revealed leucocytosis in 36.9% of patients, thrombocytosis in 8.9%, and elevated RDW in 23.6%. Notably, higher clozapine doses were associated with leucocytosis, though no significant correlations were found between clozapine dose, duration of use, and changes in RDW, mean corpuscular haemoglobin concentration, or MPV. The study's results underscore the necessity of regular haematological monitoring to mitigate the risks of clozapine therapy while leveraging its therapeutic benefits. Additionally, the study suggests personalised dosing strategies to balance efficacy and safety, particularly in managing clozapine-induced haematological changes.

Venetoclax-Based Combination Regimens in Acute Myeloid Leukemia.

In recent years, there has been tremendous interest surrounding the integration of venetoclax into both non-intensive and intensive chemotherapy regimens for AML. However, with this increasing utilization of venetoclax, considerable questions surrounding key issues such as dosing strategies and the practicality of venetoclax administration have arisen. This review highlights the evolution of venetoclax-based regimens in AML and provides a commentary on notable practical considerations when utilizing this agent.