Effect of low vs. high vancomycin trough level on the clinical outcomes of adult patients with sepsis or gram-positive bacterial infections: a systematic review and meta-analysis.

BACKGROUND & OBJECTIVE: The Infectious Disease Society of America guidelines recommend vancomycin trough levels of 15-20 mg/L for severe methicillin-resistant Staphylococcus aureus. However, recent consensus guidelines of four infectious disease organizations no longer recommend vancomycin dosing using minimum serum trough concentrations. Therefore, this study aimed to evaluate the impact of low (< 15 mg/L) vs. high (≥ 15 mg/L) vancomycin trough levels on clinical outcomes in adult patients with sepsis or gram-positive bacterial infections. METHOD: A systematic literature review from inception to December 2022 was conducted using four online databases, followed by a meta-analysis. The outcomes of interest included clinical response/efficacy, microbial clearance, length of ICU stay, treatment failure, nephrotoxicity, and mortality. RESULTS: Fourteen cohort studies met the inclusion criteria from which vancomycin trough concentration data were available for 5,228 participants. Our analysis found no association between vancomycin trough levels and clinical response [OR = 1.06 (95%CI 0.41-2.72], p = 0.91], microbial clearance [OR = 0.47 (95% CI 0.23-0.96), p = 0.04], ICU length of stay [MD=-1.01 (95%CI -5.73-3.71), p = 0.68], or nephrotoxicity [OR = 0.57 (95% CI 0.31-1.06), p = 0.07]. However, low trough levels were associated with a non-significant trend towards a lower risk of treatment failure [OR = 0.89 (95% CI 0.73-1.10), p = 0.28] and were significantly associated with reduced risk of all-cause mortality [OR = 0.74 (95% CI 0.62-0.90), p = 0.002]. CONCLUSION: Except for a lower risk of treatment failure and all-cause mortality at low vancomycin trough levels, this meta-analysis found no significant association between vancomycin trough levels and clinical outcomes in adult patients with sepsis or gram-positive bacterial infections.

Voriconazole therapeutic drug monitoring including analysis of CYP2C19 phenotype in immunocompromised pediatric patients with invasive fungal infections.

PURPOSE: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population. METHODS: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR-RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated. RESULTS: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups. CONCLUSION: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment.

Bilateral Ultrasound-Guided External Oblique Intercostal Block Vs. Modified Thoracoabdominal Nerve Block Through Perichondrial Approach for Postoperative Analgesia in Patients Undergoing Laparoscopic Sleeve Gastrectomy Surgery: A Randomized Controlled Study.

INTRODUCTION: The objective of the present study was to evaluate morphine consumption and pain scores 24 h postoperatively to compare the effects of a bilateral External Oblique Intercostal (EOI) block with those of a Modified Thoracoabdominal Nerve Block Trough Perichondrial Approach (M-TAPA) block in laparoscopic sleeve gastrectomy (LSG). METHODS: Fifty-eight patients aged between 18 and 65 years of with American Society of Anesthesiologists class II-III were included in this randomized, double-blinded study. Patients were assigned into two groups either EOI block or M-TAPA block. The primary outcome was cumulative morphine consumption within the first postoperative 24 h. Secondary outcomes were numerical rating scale (NRS) scores at rest and during activity, QoR-15 Patient Questionnaire scores, incidence of postoperative nausea and vomiting (PONV), number of patients requiring rescue analgesic and antiemetics drugs, and complications. RESULTS: There was no statistically significant difference between the groups in terms of morphine consumption in the first 24 h (EOI block; 10.74 ± 3.94 mg vs. M-TAPA block; 11.67 ± 4.66 mg, respectively). In addition, no significant difference between the two groups in the NRS and PONV scores, total QoR-15 scores, and the number of patients requiring rescue analgesics and antiemetics. CONCLUSIONS: EOI block and M-TAPA block showed similar effectiveness for morphine consumption within 24 h postoperatively and in pain scores in LSG.

Immunoglobulin therapies for primary immunodeficiency diseases (part 2): considerations for dosing strategies.

Immunoglobulin G (IgG) dosing in treating primary immunodeficiency diseases (PIDs) is individualized, which often involves regular monitoring of IgG levels, and considers patient experiences with immunoglobulin therapies, their clinical status and physician judgment. The frequency and dose(s) of intravenously (IVIG) and subcutaneously (SCIG) administered IgGs (including hyaluronidase-facilitated SCIG) require rigorous evaluation to maximize therapeutic benefits. Monitoring serum IgG levels represents an integral part of diagnosing primary immunodeficiency diseases and determining or adjusting IgG dosing strategies to meet individual patient needs, but cannot be conducted in isolation. This review discusses the current state and future perspectives on dosing strategies for different types of IgG therapies, as well as dosing considerations for specific patient populations, immunoglobulin-naive patients and patients switching between IVIG and SCIG.

Primary immunodeficiency diseases (PIDs) are a group of genetic conditions where the immune system does not work properly. Antibodies produced by the immune system help the body fight infections. PIDs can be treated with a type of antibody called immunoglobulin G (IgG), which can be given into the vein or under the skin. Determining what dose of IgG should be given to a person involves blood tests, doctors' judgment and preferences of people for how they receive treatment. Here we discuss the current strategies for choosing the right dose of IgG as well as future perspectives. We also reflect on how these methods may vary for different groups of people with PIDs, and for people starting or switching between treatments.

Detectable Concentrations With Inhaled Tobramycin in Critically Ill Infants and Children Following Implementation of Standardized Protocol.

BACKGROUND: A protocol was established for ventilator-associated tracheitis or pneumonia using inhaled tobramycin 300 mg every 12 hours in mechanically ventilated children via a vibrating mesh nebulizer, 30 cm from the endotracheal tube in the inspiratory loop of the mechanical ventilator. OBJECTIVES: The primary objective was to determine the incidence of detectable tobramycin trough concentrations >0.5 µg/mL. Secondary objectives included a comparison of clinical characteristics between those with and without detectable concentrations and identification of patients with acute kidney injury (AKI) as defined by the Kidney Diseases Improving Global Outcomes (KDIGO) criteria. METHODS: This was a single-center retrospective study of critically ill children <18 years without cystic fibrosis receiving inhaled tobramycin between July 1, 2016, and August 31, 2021. Data collection included demographics, tobramycin regimen, and renal function. Analysis was performed using SAS 9.4, with a P-value <0.05, and a multivariable regression model was performed to identify factors for detectable concentrations and AKI. RESULTS: Forty-four patients (66 courses) were included, with an overall age of 0.83 years. Thirty (68%) patients had detectable concentrations and 9 (20.5%) developed AKI. No significant differences in demographics, diagnosis, mechanical ventilation settings, and number of nephrotoxins were noted between those with and without detectable concentrations or AKI. Multivariable regressions did not identify factors associated with detectable concentrations or AKI. CONCLUSION AND RELEVANCE: Detectable concentrations occurred with the majority of courses, with AKI associated with approximately one-fourth of courses. Clinicians should consider utilizing trough monitoring for all mechanically ventilated critically ill children receiving inhaled tobramycin.

A Comparison of Vancomycin Area Under the Curve and Trough Concentration in Specific Populations.

Background: Vancomycin is an antibiotic known to cause nephrotoxicity, particularly when a vancomycin trough of 15 to 20 mg/L, a surrogate for an area under the curve (AUC) of at least 400 mgh/L, is targeted. Although monitoring vancomycin AUC is more resource intensive, it may especially benefit populations expected to be at higher risk of nephrotoxicity. Objective: To describe the proportion of discordance between vancomycin AUC and trough concentration in targeted high-risk populations. Methods: A prospective observational review was conducted on adults receiving intravenous vancomycin for more than 48 hours from May 9 to June 3, 2022. Patients included were elderly, obese, had renal dysfunction, and/or received 4 grams or more of vancomycin daily with a pending vancomycin trough concentration. A peak concentration was ordered by a project team member to calculate AUC to assess discordance. Results: A total of 47 patients were included with 87 vancomycin minimum concentration (Cmin)/AUC pairs analyzed. Discordance was observed in 52.9% of Cmin/AUC pairs in the entire cohort. The majority (79%) of the 43 Cmin levels <15 mg/L had an associated AUC >400 mgh/L and 57% of 21 Cmin levels within the 15 to 20 mg/L range had an AUC >600 mgh/L. Conclusion: A high degree of discordance between vancomycin Cmin and AUC was present in patients considered to be at high risk of nephrotoxicity. Monitoring vancomycin AUC in these patients may reduce the risk of nephrotoxicity.

Firmicutes primarily drive odor emission profiles in poultry manure treatments.

Odor emission during livestock manure treatment poses a threat to the environment and human health. However, the odor emission profiles and related factors of commonly employed poultry manure treatments have rarely been studied. Here, we explored the odor emission profiles of 3 common poultry manure treatments in China, namely, ectopic fermentation beds (EFB), annular composting troughs (ACT) and air-drying rooms (ADR). The results revealed that the total odor concentrations in the EFB, ACT and ADR groups were 2407.67 ± 512.94, 13444.00 ± 1269.92 and 621.33 ± 59.27, respectively. The ACT had the greatest number of odorants (31), followed by the ADR (27) and the EFB (24). Methyl mercaptan, acetic acid, acetaldehyde, hydrogen sulfide, ammonia and acrolein were the key odorous compounds detected in all the treatments. ACT contained the greatest number of key odorants (11) and exhibited an extensive co-occurrence relationship with the bacterial community. The 3 poultry manure treatments exhibited significant differences in the beta diversities of the bacterial community. The phylum of most bacteria associated with key odorants was Firmicutes, and Enterococcus and Oceanobacillus were significantly positively correlated with methyl mercaptan. The bacterial functional groups were enriched in carbohydrate metabolism, amino acid metabolism and energy metabolism, and the functional genes shaped the odor emission patterns in the poultry manure treatments. Redundancy analysis demonstrated that odor emission in the 3 treatments was positively correlated with Firmicutes abundance, pH, electrical conductivity and moisture. Thus, our study provides a good understanding of odor emission profiles in poultry manure treatments and data for precise odor emission control during livestock production.

Response to: Correction of Tear Trough Deformity with Minced Orbital Fat Grafts During Transconjunctival Lower Blepharoplasty.

Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Review of Association Between Urinary Tract Infections and Immunosuppressive Drugs after Heart Transplantation.

Management of infections in heart transplant recipients is complex and crucial. In this population, there is a need for a better understanding of immunosuppressive trough levels (C0), infectious complications, and urinary tract infections (UTIs). The purpose of this review was to understand the association between immunosuppressive trough levels and UTIs after heart transplantation. A review of scientific literature (n= 100) was conducted based on the topic of interest by searching PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/), Web of Science, and Scopus. The analysis of bacterial pulmonary infection required the occurrence of new or deteriorating pulmonary infiltrates and the development of organisms in cultures of sputum specimens. The diagnosis of UTIs was based on the result of related signs, pyuria, and a positive urine culture. The incidence of UTIs was reported as 0.07 episodes/1000 regarding heart transplantation days. An eightfold increase in the rate of rejection was noted in heart transplant recipients with higher variability in tacrolimus C0. There are associations between C0 of immunosuppressive drugs and clinical presentation of infection complications. Recipients with a low metabolism of immunosuppressive drugs are more susceptible to infectious complications. Attention to the biology of herpes viruses, Escherichia coli, Enterococcus spp., Pseudomonas aeruginosa, and Staphylococcus saprophyticus after heart transplantation are important, in which some of them are the most common pathogens responsible for UTIs. Pneumocystis and cytomegalovirus affect all transplant recipients. Pneumonia due to bacterial, viral, protozoa, and fungal infections, in addition to UTIs, are more specific reported types of infections in heart transplant recipients. Bacterial infections produced by extensively drug-resistant Enterobacteriaceae, vancomycin-resistant enterococci, and non-fermenting gramnegative bacteria were reported to increase after transplantation.

The interplay of knowledge, motivation, and treatment response in medication adherence among patients with chronic myeloid leukemia treated with Imatinib.

Chronic Myeloid Leukemia (CML) requires consistent medication adherence to Imatinib (IM) for optimal outcomes, however, adherence to oral chemotherapy is challenging. This observational study explores the relationship between patient knowledge, motivation, and adherence to IM therapy, and their collective impact on clinical outcomes. A prospective, observational study was conducted with 101 CML patients. The 6-Item Morisky Medication Adherence Scale (MMAS-6) was used to assess adherence, motivation, and knowledge levels. The study found that high motivation was significantly associated with lower BCR-ABL expression (p = 0.025). Patients with high knowledge and motivation had a 71% favorable response rate, compared to 0% in those with low knowledge and motivation (p = 0.01). As conclusion both patient motivation and knowledge are crucial for favorable treatment outcomes in CML. High levels of both significantly correlate with better clinical responses. Tailored interventions to enhance patient knowledge and motivation are essential.

Design of an injera baking system using parabolic trough solar collectors at Mekelle University cafeteria.

Injera baking poses a significant energy demand and strain on the national grid, requiring temperatures of 180-220 °C with traditional clay Mitads. This study aimed to design a solar thermal system to replace electrical baking energy at the Mekelle University student cafeteria. The system, designed for baking 11,000 Injera within a 6-h daily operation, comprises 92 Anodized aluminum plate Mitads heated by hot oil from an oil gallery, stored in a hot oil storage unit, and recharged via a parabolic trough solar collector. A heat exchanger and thermal storage system ensure efficient heat transfer and storage. Computational Fluid Dynamics (CFD) and Soltrace analyses were conducted to assess temperature distribution on the baking pan and oil gallery surfaces, as well as solar thermal heat flux. Results revealed a heating capacity of 2.11 kW per Mitad, meeting the required capacity, and a system energy consumption of 1216.5 MJ per hour, achieving a thermal efficiency of 57.4 %. Baking Injera at higher temperatures, enabled by a uniform temperature distribution, yielded uniformly textured Injera with an optimal number of eye bubbles and prevented sticking to the Mitad. Consequently, this design offers a viable alternative for the energy-intensive application at the Mekelle University student cafeteria, providing valuable insights for future solar thermal Injera baking system designers.

Caveolin assemblies displace one bilayer leaflet to organize and bend membranes.

Caveolin is a monotopic integral membrane protein, widely expressed in metazoa and responsible for constructing enigmatic membrane invaginations known as caveolae. Recently, the high-resolution structure of a purified human caveolin assembly, the CAV1-8S complex, revealed a unique organization of 11 protomers arranged in a tightly packed, radially symmetric spiral disc. One face and the outer rim of this disc are highly hydrophobic, suggesting that the complex incorporates into membranes by displacing hundreds of lipids from one leaflet. The feasibility of this unique molecular architecture and its biophysical and functional consequences are currently unknown. Using Langmuir film balance measurements, we find that CAV1-8S is highly surface active and intercalates into lipid monolayers. Molecular simulations of biomimetic bilayers support this 'leaflet replacement' model and reveal that while CAV1-8S effectively displaces phospholipids from one bilayer leaflet, it accumulates 40-70 cholesterol molecules into a disordered monolayer between the complex and its distal lipid leaflet. We find that CAV1-8S preferentially associates with positively curved membrane surfaces due to its influence on the conformations of distal leaflet lipids, and that these effects laterally sort lipids of the distal leaflet. Large-scale simulations of multiple caveolin assemblies confirmed their association with large, positively curved membrane morphologies, consistent with the shape of caveolae. Further, association with curved membranes regulates the exposure of caveolin residues implicated in protein-protein interactions. Altogether, the unique structure of CAV1-8S imparts unusual modes of membrane interaction with implications for membrane organization, morphology, and physiology.

Comparative assessment of trough and peak levels and AUC24 for amikacin in nontuberculous mycobacterial infection.

BACKGROUND: Amikacin, an aminoglycoside antibiotic, is widely used for the treatment of nontuberculous mycobacterial (NTM) infections. To date, therapeutic drug monitoring (TDM) of amikacin has primarily relied on the measurement of peak and trough levels as indicators rather than the 24-hr area under the concentration-time curve (AUC24). METHODS: NTM patients referred for amikacin TDM from March 2021 to May 2023 were assessed for the AUC24 values based on administered dose. We investigated re-admission rates, all-cause mortality and AFB smear results to evaluate clinical outcome based on the actual AUC24 values. Ototoxicity and nephrotoxicity were also investigated as adverse effects in correlation with TDM parameters. RESULTS: Among 65 patients, the mean and median values of AUC24 were 234 and 249 mg·hr/L, respectively. In a group of patients with AUC24 values less than 250 mg·hr/L, 42.4 % of patients were re-admitted for pulmonary symptoms. On the contrary, another group with AUC24 values equal to or more than 250 mg·hr/L, had lower re-admission rates (25.0 %). They also showed lower all-cause mortality rates and more improvement on acid-fast bacilli smear results. Moderate to poor correlation between AUC24 values and peak/trough levels were observed. Ototoxicity and nephrotoxicity were revealed to be associated with drug exposure duration rather than AUC24 values. CONCLUSION: In this study, we performed comparative assessment of trough/peak level, traditional clinical marker for amikacin TDM, and AUC24 value. Although AUC24 values showed poor to moderate correlation to trough/peak levels, higher AUC24 correlated with favorable clinical outcomes without additional risk of toxicity.

Bridging the Gap Rather Than Filling the Entire Valley-Anatomic Insights When Treating the Medial Infraorbital Region.

BACKGROUND: The treatment of the medial infraorbital region also termed the tear trough has become increasingly popular by the use of soft tissue fillers in a minimally invasive approach using a cannula. METHODS: A total of 246 tear troughs were injected and investigated originating from 123 study participants. The clinical outcome was evaluated 6 months after the treatment by independent observers based on standardized frontal images and the procedure was documented by ultrasound imaging. RESULTS: On average, 0.26 (0.1) cc [range: 0.08-0.32] of soft tissue filler material was injected per tear trough. Tear trough depth was before the treatment rated as 2.12 (0.4), whereas after the treatment it was 1.15 (0.4) (p < 0.001). Hyperpigmentation score was 2.19 (0.4) before the treatment, whereas after the treatment it was 1.31 (0.5) (p < 0.001). Intraorbital fat pseudo-prolapse severity was rated before the treatment 1.88 (0.7), whereas it was rated after the treatment 1.14 (0.3) (p < 0.001). Wrinkle severity of the lower eyelid was rated before the treatment 1.51 (0.6), whereas it was rated after the treatment 1.12 (0.3) (p < 0.001). CONCLUSION: The results of this retrospectively investigated case series revealed that the conducted injection technique for treating the tear trough for medial infraorbital hollowing with a cannula provided statistically significant clinical improvement with a limited adverse events profile. The technique utilized an injection approach which was perpendicularly oriented to the longitudinal axis of the tear trough thereby "bridging the gap instead of filling the entire valley."

Artificial intelligence-assisted grading for tear trough deformity.

BACKGROUND: Various classification systems for tear trough deformity (TTD) have been published; however, their complexity can pose challenges in clinical use, especially for less experienced surgeons. It is believed that artificial intelligence (AI) technology can address some of these challenges by reducing inadvertent errors and improving the accuracy of medical practice. In this study, we aimed to establish a reliable and precise digital image grading model for TTD using smartphone-based photography enhanced using AI deep learning technology. This model is designed to aid and guide surgeons, particularly those who are less experienced or from younger generations, during clinical examinations and in making decisions regarding further surgical interventions. MATERIALS AND METHODS: A total of 504 patients and 983 photos were included in the study. We adopted the Barton's grading system for TTD. All photos were taken using the same smartphone and processed and analyzed using the medical AI assistant (MAIA™) software. The photos were then randomly divided into two groups to establish training and testing models. RESULTS: The confusion matrix for the training model demonstrated a sensitivity of 56%, specificity of 87.3%, F1 score of 0.57, and an area under the curve (AUROC) of 0.85. For the testing group, the sensitivity was 49.3%, specificity was 85%, F1 score was 0.49, and AUROC was 0.83. Representative heatmaps were also generated. CONCLUSION: Our study is the first to demonstrate that tear trough deformities can be easily categorized using a built-in smartphone camera in conjunction with an AI deep learning program. This approach can reduce errors during clinical patient evaluations, particularly for less experienced practitioners.

Significant correlations between heavy metals and prokaryotes in the Okinawa Trough hydrothermal sediments.

Prokaryotes play crucial roles in hydrothermal vent ecosystems, yet their interactions with heavy metals are not well understood. This study explored the diversity of prokaryotic communities and their correlations with heavy metals and nutrient elements in hydrothermal sediments from Okinawa Trough. A total of 117 bacterial genera in 26 bacterial phyla and 10 archaeal classes in 3 archaeal phyla were identified, including dominant prokaryotic phyla Planctomycetes, Acidobacteria, Verrucomicrobia, and Euryarchaeota. Furthermore, Fe (39.61 mg/g), Mn (2.84 mg/g) and Ba (0.36 mg/g) were found to be the most abundant heavy metals in the Okinawa hydrothermal sediments. Notably, the concentrations of Zn, Ba, Mn, total organic carbon, and total nitrogen significantly increased, whereas the total sulfur concentration distinctively decreased at sampling sites farther from hydrothermal vents. These changes corresponded with reductions in prokaryotic abundance and diversity. Most heavy metals, including Mn, Fe, Co, Cu and As, presented significant positive correlations with a number of prokaryotic genera in the nearby sediment samples. In contrast, both positive and negative correlations with prokaryotes were observed in remote sediment. The keystone taxa include Magnetospirillum, GOUTA19, Lysobacter, Kaistobacter, Treponema, and Clostridium were detected through prokaryote interspecies interactions. The functional predictions revealed significant genes involved in carbon fixation, nitrogen/sulfur cycling, heat shock protein, and metal resistance pathways. Structural equation modeling confirmed that metal and nutrient elements directly influence the composition of prokaryotic communities, which in turn affects the relative abundance of functional genes.

Comment to: Correction of Tear Trough Deformity with Minced Orbital Fat Grafts During Transconjunctival Lower Blepharoplasty.

Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Comment to: Surgical Removal of Fat Nodules Formed in the Tear Trough After Autologous Fat Grafting.

Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Population pharmacokinetics of cyclosporine A in hematopoietic stem cell transplant recipients: A systematic review.

Cyclosporine A (CsA) is the prevalent immunosuppressive drug for preventing and treating graft-versus-host disease after hematopoietic stem cell transplantation (HSCT) in both children and adults. Population pharmacokinetic studies have identified covariates, owing to their large between-subject variability, facilitating individualized therapy. However, no review has summarized CsA's population pharmacokinetics post-HSCT. This systematic review aims to synthesize population pharmacokinetic studies of CsA therapy in HSCT recipients and explore influencing covariates. Thirteen studies, comprising five involving children, one involving both children and adults and seven involving adults, were included. The median apparent clearance in children surpassed that in adults, influenced notably by hematocrit level and body. While liver function impacted clearance, the effect was insignificant. Co-administration with cytochrome P450 enzyme inhibitors (e.g., fluconazole or itraconazole) decreased drug clearance, whereas inducers (e.g., rifampicin or rifapentine) increased it. Area under the curve analysis is recommended over trough concentration-based monitoring for HSCT recipients on CsA. In cases of insufficient trough concentration, additional sampling points are recommended for improved area under the curve estimation. Further studies are needed to evaluate the optimal sampling points required for the area under the curve estimation in CsA therapy post-HSCT.

Case report: dose-dependent interaction between dexamethasone and voriconazole in severely ill patients with non-Hodgkin's lymphoma being treated for invasive pulmonary aspergillosis.

Background: Voriconazole is primarily metabolized by CYP2C19 and CYP3A4. Drug interactions that affect this pathway can alter its plasma exposures, resulting in untargeted voriconazole concentrations. Case summary: In this case report, we describe the case of a 64-year-old man who was treated for non-Hodgkin's lymphoma with continuous glucocorticoids co-administrated with voriconazole against invasive pulmonary aspergillosis. A decrease in trough concentration (Cmin) of voriconazole was observed and related with co-administration of dexamethasone in the patient carrying the CYP2C19 *1*2 genotype: voriconazole Cmin/dose ratios of 0.018 (0.1 mg L-1/5.7 mg kg-1 day-1), 0.18 (1 mg L-1/5.7 mg kg-1 day-1), and 0.23 (2 mg L-1/8.6 mg kg-1 day-1) at dexamethasone doses of 20, 12.5, and 2.5 mg, respectively. Sub-therapeutic voriconazole Cmin was associated with high- and moderate-dose dexamethasone (20 and 12.5 mg), leading to failure of antifungal treatment. Conclusion: The extent of voriconazole-dexamethasone interaction was determined by the dose of dexamethasone and associated with the CYP2C19 *1*2 genotype. Therapeutic drug monitoring of voriconazole is necessary to avoid clinically relevant interactions for optimal antifungal therapy.