Pharmacokinetic Evaluation of Oral Viscous Budesonide in Paediatric Patients with Eosinophilic Oesophagitis in Repaired Oesophageal Atresia.

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression.

Ketogenic Diet and Progression of Kidney Disease in Animal Models of Nephropathic Cystinosis.

BACKGROUND: Nephropathic cystinosis is a rare inherited lysosomal storage disorder caused by mutations in the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. From the standpoint of the kidneys, patients develop early-onset renal Fanconi syndrome and progressive chronic kidney disease. Current therapy with cysteamine delays but does not prevent kidney failure, and has significant side effects that limit adherence and reduce the quality of life of patients. METHODS: We have tested biochemically and histologically the effects of ketogenic diet on kidney disease of two animal models of nephropathic cystinosis. RESULTS: When Ctns-/- mice were fed with ketogenic diet from 3 to 12 months of age, we observed significant nearly complete prevention of Fanconi syndrome, including low molecular weight proteinuria, glycosuria and polyuria. Compared to wild-type animals, BUN at 12 months was higher in cystinotic mice fed with standard diet (P<0.001), but not with ketogenic diet. At sacrifice, kidneys of knock out mice fed with ketogenic diet appeared macroscopically similar to those of wild type animals, which was reflected microscopically by a significant reduction of interstitial cell infiltration (CD3 and CD68 positive cells, P<0.01), of interstitial fibrosis (Masson and α-SMA staining, P< 0.001), and of apoptosis (cleaved caspase 3 levels; P<0.001), and by indirect evidence of restoration of a normal autophagic flux (SQSTM1/p62 and LC3-II expression, P<0.05). Beneficial effects of ketogenic diet on tubular function were also observed after mice were fed with this ketogenic diet from the age of 6 months to the age of 15 months, after they had developed proximal tubular dysfunction. Although slightly less pronounced, these results were replicated in Ctns-/- rats fed with ketogenic diet from 2 to 8 months of life. CONCLUSIONS: These results indicate significant mitigation of the kidney phenotype in cystinotic animals fed with ketogenic diet.

A New and Rapid LC-MS/MS Method for the Determination of Cysteamine Plasma Levels in Cystinosis Patients.

Cystinosis is a rare lysosomal storage disorder caused by autosomal recessive mutations in the CTNS gene that encodes for the cystine transporter cystinosin, which is expressed on the lysosomal membrane mediating the efflux of cystine. Cysteamine bitartrate is a cystine-depleting aminothiol agent approved for the treatment of cystinosis in children and adults. In this study, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of cysteamine levels in plasma samples. This LC-MS/MS method was validated according to the European Medicines Agency (EMA)'s guidelines for bioanalytical method validation. An ultra-performance liquid chromatograph (UPLC) coupled with a 6470 mass spectrometry system was used for cysteamine determination. Our validated method was applied to plasma samples from n = 8 cystinosis patients (median, interquartile range (IQR) = 20.5, 8.5-26.0 years). The samples were collected before cysteamine oral administration (pre-dose) and 1 h after (post-dose). Our bioanalytical method fulfilled the regulatory guidelines for method validation. The cysteamine plasma levels in pre-dose samples were 2.57 and 1.50-3.31 µM (median and IQR, respectively), whereas the post-dose samples reported a cysteamine median concentration of 28.00 µM (IQR: 17.60-36.61). Our method allows the rapid determination of cysteamine plasma levels. This method was successfully used in cystinosis patients and, therefore, could be a useful tool for the evaluation of therapy adherence and for future pharmacokinetic (PK) studies involving a higher number of subjects.

Simultaneous post-neurosurgical ventriculitis and bacteraemia by two different strains of KPC-producing K. pneumoniae successfully treated with meropenem/vaborbactam and high dose of fosfomycin.

OBJECTIVE: A case of post-neurosurgical ventriculitis caused by a KPC-producing Klebsiella pneumoniae (KPC-Kp) with a ceftazidime/avibactam-resistant, meropenem-susceptible phenotype is reported. METHODS AND RESULTS: The patient had a concomitant bloodstream infection with a wild-type KPC-Kp with a ceftazidime/avibactam-susceptible, meropenem-resistant phenotype. Prolonged treatment with intravenous fosfomycin and meropenem/vaborbactam achieved clinical success. Therapeutic drug monitoring performed during the first days of treatment showed for the first time that vaborbactam efficiently penetrates cerebrospinal fluid. In contrast, meropenem was undetectable in cerebrospinal fluid at each sampling, suggesting that additional doses of meropenem may be required to appropriately prescribe meropenem/vaborbactam for central nervous system infections. Plasma and cerebrospinal fluid levels of fosfomycin were adequate, confirming the potential of this agent possibly even in the fight against multidrug-resistant organisms. CONCLUSIONS: This case highlights the need for therapeutic drug monitoring as a crucial tool for optimizing treatment in complicated cases where the pharmacokinetic behaviour of antibiotics is difficult to predict.

MFSD12 depletion reduces cystine accumulation without improvement in proximal tubular function in experimental models for cystinosis.

Cystinosis is an autosomal recessive lysosomal storage disorder, caused by mutations in the CTNS gene, resulting in an absent or altered cystinosin (CTNS) protein. Cystinosin exports cystine out of the lysosome, with a malfunction resulting in cystine accumulation and a defect in other cystinosin-mediated pathways. Cystinosis is a systemic disease, but the kidneys are the first and most severely affected organs. In the kidney, the disease initially manifests as a generalized dysfunction in the proximal tubules (also called renal Fanconi syndrome). MFSD12 is a lysosomal cysteine importer that directly affects the cystine levels in melanoma cells, HEK293T cells, and cystinosis patient-derived fibroblasts. In this study, we aimed to evaluate MFSD12 mRNA levels in cystinosis patient-derived proximal tubular epithelial cells (ciPTECs) and to study the effect of MFSD12 knockout on cystine levels. We showed similar MFSD12 mRNA expression in patient-derived ciPTECs in comparison with the control cells. CRISPR MFSD12 knockout in a patient-derived ciPTEC (CTNSΔ57kb) resulted in significantly reduced cystine levels. Furthermore, we evaluated proximal tubular reabsorption after injection of mfsd12a translation-blocking morpholino (TB MO) in a ctns-/- zebrafish model. This resulted in decreased cystine levels but caused a concentration-dependent increase in embryo dysmorphism. Furthermore, the mfsd12a TB MO injection did not improve proximal tubular reabsorption or megalin expression. In conclusion, MFSD12 mRNA depletion reduced cystine levels in both tested models without improvement of the proximal tubular function in the ctns-/- zebrafish embryo. In addition, the apparent toxicity of higher mfsd12a TB MO concentrations on the zebrafish development warrants further evaluation.NEW & NOTEWORTHY In this study, we show that MFSD12 depletion with either CRISPR/Cas9-mediated gene editing or a translation-blocking morpholino significantly reduced cystine levels in cystinosis ciPTECs and ctns-/- zebrafish embryos, respectively. However, we observed no improvement in the proximal tubular reabsorption of dextran in the ctns-/- zebrafish embryos injected with mfsd12a translation-blocking morpholino. Furthermore, a negative effect of the mfsd12a morpholino on the zebrafish development warrants further investigation.

Father-to-daughter transmission in late-onset OTC deficiency: an underestimated mechanism of inheritance of an X-linked disease.

BACKGROUND: Ornithine Transcarbamylase Deficiency (OTCD) is an X-linked urea cycle disorder characterized by acute hyperammonemic episodes. Hemizygous males are usually affected by a severe/fatal neonatal-onset form or, less frequently, by a late-onset form with milder disease course, depending on the residual enzymatic activity. Hyperammonemia can occur any time during life and patients could remain non- or mis-diagnosed due to unspecific symptoms. In heterozygous females, clinical presentation varies based on the extent of X chromosome inactivation. Maternal transmission in X-linked disease is the rule, but in late-onset OTCD, due to the milder phenotype of affected males, paternal transmission to the females is possible. So far, father-to-daughter transmission of OTCD has been reported only in 4 Japanese families. RESULTS: We identified in 2 Caucasian families, paternal transmission of late-onset OTCD with severe/fatal outcome in affected males and 1 heterozygous female. Furthermore, we have reassessed the pedigrees of other published reports in 7 additional families with evidence of father-to-daughter inheritance of OTCD, identifying and listing the family members for which this transmission occurred. CONCLUSIONS: Our study highlights how the diagnosis and pedigree analysis of late-onset OTCD may represent a real challenge for clinicians. Therefore, the occurrence of paternal transmission in OTCD should not be underestimated, due to the relevant implications for disease inheritance and risk of recurrence.

Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis.

Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to treat the genetic defect in cystinosis using synthetic mRNA in cell models and ctns-/- zebrafish embryos. Cystinosis is a prototype lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal cystine-H+ symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and the most severely affected organs, presenting glomerular and proximal tubular dysfunction, progressing to end-stage kidney failure. The current therapeutic standard cysteamine, reduces cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA can restore lysosomal cystinosin expression following lipofection into CTNS-/- kidney cells and injection into ctns-/- zebrafish. A single CTNS mRNA administration decreases cellular cystine accumulation for up to 14 days in vitro. In the ctns-/- zebrafish, CTNS mRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. Therefore, this proof-of-principle study takes the first steps in establishing an mRNA-based therapy to restore cystinosin expression, resulting in cystine reduction in vitro and in the ctns-/- larvae, and restoration of the zebrafish pronephros function.

Utilization of volumetric absorptive microsampling and dried plasma spot for quantification of anti-fungal triazole agents in pediatric patients by using liquid chromatography-tandem mass spectrometry.

BACKGROUND: Recently, increasing attention has been paid to the use of microsampling techniques for therapeutic drug monitoring (TDM) in neonatal and pediatric populations. Volumetric Absorptive Microsampling (VAMS) has been introduced in the market under the name Mitra® (Neoteryx). These devices consist of porous absorbent tips that allow collection of fixed blood volumes (10-30 µL) to overcome the DBS-related hematocrit effect. Here, the authors analyzed the concentrations of triazole agents (voriconazole, posaconazole, and isavuconazole) in VAMS and dried plasma spot (DPS) samples. METHODS: Fifty whole blood samples were obtained from pediatric patients subjected to systemic anti-fungal therapy. VAMS were collected by dipping the tip into whole blood before centrifugation for plasma recovery. Then, 30 µL of plasma was carefully spotted on filter paper to obtain DPS. Anti-fungal concentrations were measured using a validated LC-MS/MS kit (MassTox® Antimycotic Drugs/EXTENDED) provided by Chromsystems (Chromsystems Instruments & Chemicals). Drug concentrations in VAMS and DPS samples were compared to those in fresh plasma using Passing-Bablok and Bland-Altman tests. RESULTS: Plasma concentrations of voriconazole, posaconazole, and isavuconazole were positively and significantly correlated with those obtained in VAMS and DPS samples (Spearman r range, 0.82-0.94, p < 0.001). Data were further analyzed using the Bland-Altman test, which showed a % mean difference compared to fresh plasma of -15.06-10.98 (range). The stability of both VAMS and DPS was ensured for at least 14 d at room temperature. CONCLUSIONS: These results demonstrate that VAMS and DPS can be used for the TDM of anti-fungal agents. Owing to their stability, both sampling devices can be easily stored and shipped, without the need for refrigeration, to TDM laboratories that facilitate remote TDM applications. Finally, VAMS could be particularly suitable for pediatric and neonatal patients because they allow the collection of a few microliters of blood, thus improving ethical and compliance limitations.

Impact of Continuous Kidney Replacement Therapy and Hemoadsorption with CytoSorb on Antimicrobial Drug Removal in Critically Ill Children with Septic Shock: A Single-Center Prospective Study on a Pediatric Cohort.

Background: Extracorporeal therapies (ET) are increasingly used in pediatric settings as adjuvant therapeutic strategies for overwhelming inflammatory conditions. Although these treatments seem to be effective for removing inflammatory mediators, their influence on antimicrobials pharmacokinetic should not be neglected. Methods: A prospective observational study of children admitted to the pediatric intensive care unit (PICU) with a diagnosis of sepsis/septic shock. All critically ill children received hemoadsorption treatment with CytoSorb (CS) in combination with CKRT. Therapeutic drug monitoring has been performed on 10 critically ill children, testing four antimicrobial molecules: meropenem, ceftazidime, amikacin and levofloxacin. In order to evaluate the total and isolated CKRT and CS contributions to antibiotic removal, blood samples at each circuit point (post-hemofilter, post-CS and in the effluent line) were performed. Therefore, the clearance and mass Removal (MR) of the hemofilter and CS were calculated. Results: Our preliminary report describes a different impact of CS on these target drugs removal: CS clearance was low for amikacine (6-12%), moderate for ceftazidime (43%) and moderate to high for levofloxacine (52-72%). Higher MR and clearance were observed with CKRT compared to CS. To the best of our knowledge, this is the first report regarding pharmacokinetic dynamics in critically ill children treated with CKRT and CS for septic shock.

Continuous Fentanyl Infusion in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia: Background, Aims, and Study Protocol for Time-Concentration Profiles.

Therapeutic hypothermia (TH) is the standard of care for newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE). Discomfort and pain during treatment are common and may affect the therapeutic efficacy of TH. Opioid sedation and analgesia (SA) are generally used in clinical practice, and fentanyl is one of the most frequently administered drugs. However, although fentanyl's pharmacokinetics (PKs) may be altered by hypothermic treatment, the PK behavior of this opioid drug in cooled newborns with HIE has been poorly investigated. The aim of this phase 1 study protocol (Trial ID: FentanylTH; EUDRACT number: 2020-000836-23) is to evaluate the fentanyl time-concentration profiles of full-term newborns with HIE who have been treated with TH. Newborns undergoing TH receive a standard fentanyl regimen (2 mcg/Kg of fentanyl as a loading dose, followed by a continuous infusion-1 mcg/kg/h-during the 72 h of TH and subsequent rewarming). Fentanyl plasma concentrations before bolus administration, at the end of the loading dose, and 24-48-72-96 h after infusion are measured. The median, maximum, and minimum plasma concentrations, together with drug clearance, are determined. This study will explore the fentanyl time-concentration profiles of cooled, full-term newborns with HIE, thereby helping to optimize the fentanyl SA dosing regimen during TH.

Oral Viscous Budesonide in Children With Eosinophilic Esophagitis After Repaired Esophageal Atresia: A Clinical Trial.

OBJECTIVES: A high prevalence of eosinophilic esophagitis (EoE) has been reported in children with repaired esophageal atresia (EA). Topical steroids proved to be an effective and safe therapy in EoE, although not approved in pediatrics. We report the results of the first clinical trial of oral viscous budesonide (OVB) performed in children with EoE after repaired esophageal atresia (EoE-EA). METHODS: This open-label, single-arm, phase 2 clinical trial with randomized pharmacokinetic sampling, was conducted at the Bambino Gesù Children's Hospital between September 2019 and June 2021. EoE-EA patients received an age-banded dose of OVB twice daily for 12 weeks and were endoscopically evaluated. The primary endpoint was the rate of patients achieving histological remission. Secondary endpoints included clinical and endoscopic benefit after treatment, and safety assessments. RESULTS: Eight consecutive EA-EoE patients were enrolled (median age 9.1 years, interquartile range 5.5). Of these, 5 received 0.8 mg and 3 received 1.0 mg twice daily of OVB. Histological remission was obtained in all but 1 patient (87.5%). The clinical score showed significant improvement at the end of treatment in all patients. No endoscopic features of EoE were found after treatment. No treatment-emergent adverse event occurred. CONCLUSION: OVB is an effective, safe, and well-tolerated formulation of budesonide for use in pediatric patients with EoE-EA.

Plasma and Cerebrospinal Fluid Concentrations of Micafungin Administered at High Doses in Critically Ill Infants with Systemic Candidiasis: A Pooled Analysis of Two Studies.

Background: Neonates may require higher doses of micafungin than adults to reach the therapeutic effect for increased plasma clearance. Only poor and inconclusive data are available still now to support this hypothesis, especially with regard to central nervous system micafungin concentrations. To assess the pharmacokinetics of increased doses (8 to 15 mg/kg/day) of micafungin in preterm and term neonates with invasive candidiasis and to complete previously presented results, we analyzed the pharmacokinetic data on a total of 53 newborns treated with micafungin, whereby 3 of them had Candida meningitis and hydrocephalus. Methods: Fifty-three neonates with systemic candidiasis, three of them with meningitis, were treated for at least 14 days with intravenous micafungin (Mycamine®) at a dosage ranging from 8 to 15 mg/kg/day. Plasma and cerebrospinal fluid (CSF) concentrations of micafungin were measured before the drug administration and at 1, 2, and 8 h after the end of the infusion using high-performance liquid chromatography (HPLC). Systemic exposure was assessed according to AUC0-24, plasma clearance (CL), and half-life measured in 52/53 patients, divided by chronological age. Results and conclusions: The mean micafungin clearance is higher in neonates than in older infants (0.036 L/h/kg before 28 days of life versus 0.028 L/h/kg after 120 days). The drug half-life is shorter in neonates than in older patients (13.5 h before 28 days of life versus 14.4 h after 120 days). With doses ranging between 8 and 15 mg/kg/day, micafungin crosses the blood-brain barrier reaching therapeutic levels in CSF.

Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine.

Cysteamine is currently the only therapy for nephropathic cystinosis. It significantly improves life expectancy and delays progression to end-stage kidney disease; however, it cannot prevent it. Unfortunately, compliance to therapy is often weak, particularly during adolescence. Therefore, finding better treatments is a priority in the field of cystinosis. Previously, we found that genistein, an isoflavone particularly enriched in soy, can revert part of the cystinotic cellular phenotype that is not sensitive to cysteamine in vitro. To test the effects of genistein in vivo, we fed 2-month-old wild-type and Ctns-/- female mice with either a control diet, a genistein-containing diet or a cysteamine-containing diet for 14 months. Genistein (160 mg/kg/day) did not affect the growth of the mice or hepatic functionality. Compared with untreated mice at 16 months, Ctns-/- mice fed with genistein had lower cystine concentrations in their kidneys, reduced formation of cystine crystals, a smaller number of LAMP1-positive structures and an overall better-preserved parenchymal architecture. Cysteamine (400 mg/kg/day) was efficient in reverting the lysosomal phenotype and in preventing the development of renal lesions. These preclinical data indicate that genistein ameliorates kidney injury resulting from cystinosis with no side effects. Genistein therapy represents a potential treatment to improve the outcome for patients with cystinosis.

The Use of Cefiderocol as Salvage Therapy in an Infant Receiving ECMO and Continuous Renal Replacement Therapy.

BACKGROUND: Infections caused by antimicrobial-resistant (AMR) pathogens are increasing worldwide, representing a serious global public health issue with high morbidity and mortality rates The treatment of Pseudomonas aeruginosa (PA) infections has become a significant challenge due to its ability to develop resistance to many of the currently available antibiotics, especially in intensive care unit (ICU) settings. Among the very few therapeutic lines available against extensively drug-resistant (XDR)-PA and/or with difficult-to-treat resistance (DTR)-PA, cefiderocol is an injectable siderophore cephalosporin not licensed for use in pediatric patients. There are only a few case reports and two ongoing trials describing the administration of this cephalosporin in infants. CASE PRESENTATION: This report describes the case of a critically ill 8-month-old girl affected by ventilator-associated pneumonia (VAP) infection complicated by bloodstream infection (BSI) sustained by VIM-producing PA. She was treated with cefiderocol as a salvage therapy during ECMO and CRRT support. CONCLUSIONS: In healthcare settings, treating multidrug-resistant, Gram-negative bacteria poses a serious challenge, especially in pediatric patients. Our findings suggest that cefiderocol can be considered as an off-label rescue therapy in selected pediatric cases.

Therapeutic Drug Monitoring of Quinidine in Pediatric Patients with KCNT1 Genetic Variants.

Quinidine (QND) is an old antimalarial drug that was used in the early 20th century as an antiarrhythmic agent. Currently, QND is receiving attention for its use in epilepsy of infancy with migrating focal seizures (EIMFS) due to potassium sodium-activated channel subfamily T member 1 (KCNT1) genetic variants. Here, we report the application of Therapeutic Drug Monitoring (TDM) in pediatric patients carrying KCNT1 genetic variants and orally treated with QND for developmental and epileptic encephalopathies (DEE). We measured plasma levels of QND and its metabolite hydroquinidine (H-QND) by using a validated method based on liquid chromatography coupled with mass spectrometry (LC-MS/MS). Three pediatric patients (median age 4.125 years, IQR 2.375-4.125) received increasing doses of QND. Cardiac toxicity was monitored at every dose change. Reduction in seizure frequency ranged from 50 to 90%. Our results show that QND is a promising drug for pediatric patients with DEE due to KCNT1 genetic variants. Although QND blood levels were significantly lower than the therapeutic range as an anti-arrhythmic drug, patients showed a significant improvement in seizure burden. These data underlie the utility of TDM for QND not only to monitor its toxic effects but also to evaluate possible drug-drug interactions.

Use of Antibiotics in Preterm Newborns.

Due to complex maturational and physiological changes that characterize neonates and affect their response to pharmacological treatments, neonatal pharmacology is different from children and adults and deserves particular attention. Although preterms are usually considered part of the neonatal population, they have physiological and pharmacological hallmarks different from full-terms and, therefore, need specific considerations. Antibiotics are widely used among preterms. In fact, during their stay in neonatal intensive care units (NICUs), invasive procedures, including central catheters for parental nutrition and ventilators for respiratory support, are often sources of microbes and require antimicrobial treatments. Unfortunately, the majority of drugs administered to neonates are off-label due to the lack of clinical studies conducted on this special population. In fact, physiological and ethical concerns represent a huge limit in performing pharmacokinetic (PK) studies on these subjects, since they limit the number and volume of blood sampling. Therapeutic drug monitoring (TDM) is a useful tool that allows dose adjustments aiming to fit plasma concentrations within the therapeutic range and to reach specific drug target attainment. In this review of the last ten years' literature, we performed Pubmed research aiming to summarize the PK aspects for the most used antibiotics in preterms.

Biomarkers in Nephropathic Cystinosis: Current and Future Perspectives.

Early diagnosis and effective therapy are essential for improving the overall prognosis and quality of life of patients with nephropathic cystinosis. The severity of kidney dysfunction and the multi-organ involvement as a consequence of the increased intracellular concentration of cystine highlight the necessity of accurate monitoring of intracellular cystine to guarantee effective treatment of the disease. Cystine depletion is the only available treatment, which should begin immediately after diagnosis, and not discontinued, to significantly slow progression of renal and extra-renal organ damage. This review aims to discuss the importance of the close monitoring of intracellular cystine concentration to optimize cystine depletion therapy. In addition, the role of new biomarkers in the management of the disease, from timely diagnosis to implementing treatment during follow-up, is overviewed.

Therapeutic Drug Monitoring of Amphotericin-B in Plasma and Peritoneal Fluid of Pediatric Patients after Liver Transplantation: A Case Series.

Fungal infections represent a serious complication during the post-liver transplantation period. Abdominal infections can occur following pre-existing colonization, surgical procedures, and permanence of abdominal tubes. In our center, liposomal amphotericin-B is used as antifungal prophylaxis in pediatric patients undergoing liver transplantation. The aim of this study is to evaluate peritoneal levels of amphotericin-B following intravenous administration. Six liver recipients received liposomal amphotericin-B. Three of them were treated as prophylaxis; meanwhile, three patients received liposomal amphotericin-B to treat Candida albicans infection. Plasma and peritoneal amphotericin-B levels were measured by LC-MS/MS in two consecutive samplings. Cmin (pre-dose) and Cmax (2 h after the end of infusion) were evaluated as drug exposure parameters for both plasma and peritoneum. Our results showed that peritoneal amphotericin-B levels were significantly lower than plasma and that the correlation coefficient was 0.72 (p = 0.03) between plasma and peritoneal Cmin. Moreover, although peritoneal levels were within the therapeutic range, they never reached the PK/PD target (Cmax/MIC > 4.5). In conclusion, PK exposure parameters could be differently used to analyze amphotericin-B concentrations in plasma and peritoneum. However, liposomal amphotericin-B should be preferred in these patients as prophylactic rather than therapeutic treatment for fungal infections.

Use of Meropenem and Other Antimicrobial Lock Therapy in the Treatment of Catheter-Related Blood Stream Infections in Neonates: A Retrospective Study.

(1) Background: Newborns admitted to Neonatal Intensive Care Units (NICUs) often require the placement of central vascular catheters (CVC), which are a major risk factor for hospital infection. Numerous strategies exist to prevent central line-associated blood stream infections (CLABSIs) and catheter-related bloodstream infections (CRBSIs), with only a few offering options to save the catheter when it is impossible to replace. CRBSIs continue to be a major problem for neonates in NICUs. Most CRBSIs are resistant to systemic antibiotics due to the presence of intraluminal bacterial biofilm. Therefore, catheter removal is frequently necessary when a CRBSI occurs. The so-called Antibiotic Lock Therapy (ALT) is an antimicrobial therapeutic strategy which seems to be promising in neonates when catheter removal is difficult due to critical conditions. To date, evidence about the use of ALT in the neonatal period is still fragmentary, since only poor and heterogeneous data exist. (2) Methods: We report our successful experience with ALT in seriously ill neonates with CRBSI for whom the replacement of the catheter could have been life threatening. (3) Results: ALT repetitively performed for at least 12 h was effective in 11 out of 13 infants (84.6%). It was not effective in two infants in whom ALT was performed for only 6 h. Moreover, we present new data about the stability testing of meropenem for its use during ALT in neonates. (4) Conclusions: When CRBSI occurs-bearing in mind that the optimal management is catheter removal if antibiotic therapy is not effective within 48 h-ALT seems to be a valid alternative therapy when removal is impractical due to critical conditions.

Smartphone-assisted electrochemical sensor for reliable detection of tyrosine in serum.

Point-of-care devices have attracted a huge interest by the scientific community because of the valuable potentiality for rapid diagnosis and precision medicine through cost-effective and easy-to-use devices for on-site measurement by unskilled personnel. Herein, we reported a smartphone-assisted electrochemical device consisted of a screen-printed electrode modified with carbon black nanomaterial and a commercially available smartphone potentiostat i.e. EmStat3 Blue, for sensitive detection of tyrosine. Once optimized the conditions, tyrosine was detected in standard solutions by square wave voltammetry, achieving a linear range comprised between 30 and 500 µM, with a detection limit equal to 4.4 µM. To detect tyrosine in serum, the interference of another amino acid i.e. tryptophan was hindered using a sample treatment with an extraction cartridge. The agreement of results analyzing serum samples with HPLC reference method and with the developed smart sensing system demonstrated the suitability of this smartphone-assisted sensing tool for cost-effective and rapid analyses of tyrosine in serum samples.