AmBisome® Formulations for Pediatrics: Stability, Cytotoxicity, and Cost-Effectiveness Studies.

Liposomal amphotericin B (Ambisome®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be challenging due to the spontaneous tendency of amphotericin B to form aggregates with different biological activity. In this study, the colloidal stability of the liposomes and the chemical stability of amphotericin B were investigated over time at storage conditions. Three liposomal formulations of amphotericin B at 4.0 mg/mL, 2.0 mg/mL, and 0.2 mg/mL were prepared and assayed for changes regarding the dimensional distribution, zeta potential, drug aggregation state, and onset of by-products. Our analyses highlighted that the most diluted formulation, kept at room temperature, showed the greatest changes in the aggregation state of the drug and accordingly the highest cytotoxicity. These findings are clinically relevant since the lower dosages are addressed to the more vulnerable patients. Therefore, the centralization of the dilution of AmBisome® at the pharmacy is of fundamental importance for assuring patient safety, and at the same time for reducing medication waste, as we demonstrated using the cost-saving analysis of drug expense per therapy carried out at the G. Gaslini children hospital.

Antibiotic defined daily dose in pediatrics. A single center study to proof the principle that a specific pediatric definition could be not needed / Dosis diaria definida de antibiótico en Pediatría. Un estudio de centro único para probar de que una definición pediátrica especifica podría no ser necesaria

Objectives: To evaluate if a specific pediatric defined daily dose (PeDDD) can be replaced with the defined daily dose (DDD) indicated by World Health Organization (WHO). Methods: The 50th percentile of body weight for age of children admitted from 2016 to 2020 at Istituto Giannina Gaslini, Genoa, Italy, was used to calculate PeDDD for vancomycin at 40mg/kg and meropenem at 60mg/kg. Data obtained were then used to calculate the PeDDD number based on the amount of drugs delivered quarterly from 2012 to 2016. Subsequently the DDD number was calculated for vancomycin at 2g and meropenem at 3g. With these results two curves were generated which were then compared for parallelism and area under the curve (AUC). Results: PeDDD was found to be 2.6 times DDD for both drugs, but both curves obtained were parallel and the AUCs were identical.Conclusions: DDD according to WHO definition could be adopted in pediatrics to measure antibiotic consumption and therefore no specific PeDDD could be needed.(AU)

Objetivos: Evaluar si una dosis diaria definida pediátrica específica (PeDDD) puede ser reemplazada por la dosis diaria definida (DDD) indicada por la Organización Mundial de la Salud (OMS). Métodos: El 50 percentil del peso por la edad media de los niños admitidos desde 2016 hasta 2020 al Istituto Giannina Gaslini, Génova, Italia, fue utilizado para calcular el PeDDD con vancomina a 40mg/kg y meropenem a 60mg/kg. Luego los datos obtenidos fueron utilizados para calcular el número de PeDDD basado en la cantidad de medicamentos entregados trimestralmente desde 2012 hasta 2016. Posteriormente, el número de DDD fue calculado con vancomicina a 2g y meropenem a 3g. Con los resultados, se generaron 2 curvas que fueron comparadas con paralelismo y área bajo la curva (AUC). Resultados: PeDDD resultó ser 2,6 veces DDD por ambos medicamentos, pero ambas curvas obtenidas eran paralelas y las AUC eran idénticas. Conclusiones: DDD, según la definición de la OMS, podría adoptarse en Pediatría para medir el consumo de antibióticos y, por lo tanto, no podría ser necesario un PeDDD específico.(AU)

Changes in the Use of Antibiotics for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections in Children: A 5-Year Retrospective, Single Center Study.

Monitoring antibiotic use in the pediatric population is a challenge, especially when determining a relationship between specific pathogens, infections, and antibiotic use. We retrospectively analyzed the consumption of anti-methicillin-resistant Staphylococcus aureus (MRSA) drugs from 2017 to 2021 at Istituto Giannina Gaslini by means of defined daily dose (DDD) adopted for adults by World Health Organization. We observed a statistically significant increase in the use of daptomycin and ceftaroline, combined with a decrease in the use of vancomycin. In the same period, we observed an increase in the proportion of bloodstream infections due to MRSA with vancomycin minimally inhibitory concentration (MIC mg/L) = 1, that represented the 100% of cases in 2021. This aspect was combined with the observation that in the 59% of cases, where vancomycin plasma concentrations were evaluated, it was not possible to achieve a ratio of the 24-h area under the concentration-time curve and MIC (AUC0-24/MIC) of vancomycin ≥ 400 mg/L. This study confirms that DDD can be used in pediatrics to monitor antibiotic consumption in relationship with infections epidemiology. Moreover, it describes the presence of vancomycin MIC creep for MRSA also in pediatrics and the difficulties in obtaining effective vancomycin plasma concentrations in children.

Antibiotic defined daily dose in pediatrics. A single center study to proof the principle that a specific pediatric definition could be not needed.

OBJECTIVES: To evaluate if a specific pediatric defined daily dose (PeDDD) can be replaced with the defined daily dose (DDD) indicated by World Health Organization (WHO). METHODS: The 50th percentile of body weight for age of children admitted from 2016 to 2020 at Istituto Giannina Gaslini, Genoa, Italy, was used to calculate PeDDD for vancomycin at 40mg/kg and meropenem at 60mg/kg. Data obtained were then used to calculate the PeDDD number based on the amount of drugs delivered quarterly from 2012 to 2016. Subsequently the DDD number was calculated for vancomycin at 2g and meropenem at 3g. With these results two curves were generated which were then compared for parallelism and area under the curve (AUC). RESULTS: PeDDD was found to be 2.6 times DDD for both drugs, but both curves obtained were parallel and the AUCs were identical CONCLUSIONS: DDD according to WHO definition could be adopted in pediatrics to measure antibiotic consumption and therefore no specific PeDDD could be needed.

Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics.

In the treatment of pediatric diseases, mass-produced dosage forms are often not suitable for children. Commercially available medicines are commonly manipulated and mixed with food by caregivers at home, or extemporaneous medications are routinely compounded in the hospital pharmacies to treat hospitalized children. Despite considerable efforts by regulatory agencies, the pediatric population is still exposed to questionable and potentially harmful practices. When designing medicines for children, the ability to fine-tune the dosage while ensuring the safety of the ingredients is of paramount importance. For these purposes solid formulations may represent a valid alternative to liquid formulations for their simpler formula and more stability, and, to overcome the problem of swelling ability, mini-tablets could be a practicable option. This review deals with the different approaches that may be applied to develop mini-tablets intended for pediatrics with a focus on the safety of excipients. Alongside the conventional method of compression, 3D printing appeared particularly appealing, as it allows to reduce the number of ingredients and to avoid both the mixing of powders and intermediate steps such as granulation. Therefore, this technique could be well adaptable to the daily galenic preparations of a hospital pharmacy, thus leading to a reduction of the common practice of off-label preparations.

Da Vinci Robotic Surgery in a Pediatric Hospital.

INTRODUCTION: Since the use of robotic surgery (RS) revolutionized some adult surgery procedures such as radical prostatectomy, it has been progressively and increasingly introduced in pediatric surgery. The aim of this study is to evaluate how the Da Vinci® Si HD technology impacts a pediatric public hospital and to define the use of a robotic system in pediatric surgery. MATERIALS AND METHODS: We prospectively included patients older than 6 months of age undergoing RS or conventional minimal access surgery (MAS): Study period ranges between February 2015 and April 2016. Surgical indications were defined after a detailed disease-specific diagnostic work-up. We analyzed surgical outcomes and the most relevant economic aspects. The 30-day postoperative complications were evaluated and retrospectively collected in an electronic database. RESULTS: From February 2015 to April 2016, we performed 77 procedures with RS and 84 with conventional MAS in patients with a median age of 77 and 98 months at surgery and a median weight of 20 and 23 kg, respectively. Median operative times were 130 and 109 minutes, respectively. We observed 9.1% of complications in the RS group and 6% in the MAS group and the difference was not statistically significant. Of note, 8 out of 77 RS procedures would have been performed with open classic surgery in case of conversion or failure of RS. CONCLUSIONS: This initial experience confirms that RS is as safe and effective as conventional MAS. A number of selected procedures performed with RS would only benefit from this approach, as it is not suitable for conventional MAS. Although economically demanding, in particular for a pediatric hospital, we firmly believe that centralization of care would allow pediatric surgeons adopting RS to perform complex reconstructive surgical procedures with great advantages for the patients and a minimal increase in overall costs for the health system.

Henoch-Schönlein purpura and drug and vaccine use in childhood: a case-control study.

BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood; nevertheless, its etiology and pathogenesis remain unknown despite the fact that a variety of factors, mainly infectious agents, drugs and vaccines have been suggested as triggers for the disease. The aim of this study was to estimate the association of HSP with drug and vaccine administration in a pediatric population. METHODS: An active surveillance on drug and vaccine safety in children is ongoing in 11 clinical centers in Italy. All children hospitalized through the local Paediatric Emergency Department for selected acute clinical conditions of interest were enrolled in the study. Data on drug and vaccine use in children before the onset of symptoms leading to hospitalization were collected by parents interview. A case-control design was applied for risk estimates: exposure in children with HSP, included as cases, was compared with similar exposure in children with gastroduodenal lesions, enrolled as controls. HSP cases were validated according to EULAR/PRINTO/PRES criteria. Validation was conducted retrieving data from individual patient clinical record. RESULTS: During the study period (November 1999-April 2013), 288 cases and 617 controls were included. No increased risk of HSP was estimated for any drug. Among vaccines, measles-mumps-rubella (MMR) vaccine showed an increased risk of HSP (OR 3.4; 95 % CI 1.2-10.0). CONCLUSIONS: This study provides further evidence on the possible role of MMR vaccine in HSP occurrence.

A practical approach to the use of low molecular weight heparins in VTE treatment and prophylaxis in children and newborns.

Low-molecular weight heparins are currently the most commonly used anticoagulants in children and newborns. However, since thrombotic complications rarely occur outside large children's hospitals, physicians often encounter some practical problems in managing these treatments when a pediatric thrombosis specialist is not available. The drug of choice is enoxaparin, due to its favorable FXa/FIIa ratio and the availability of pharmacokinetic and pharmacodynamic data. The treatment of acute thrombosis should be started with two daily injections but when compliance is an issue, a single daily administration schedule could be chosen for secondary prophylaxis ensuring careful measurement of the post 24-hour anti-FXa activity. Furthermore, a subcutaneous device may be a useful tool and a topical dermal anesthetic could be effective in controlling pain without affecting anti-FXa levels. In neonate and toddlers, where mini doses are frequently needed, the dead space of syringes and needles could represent an issue and therefore the use of insulin syringes without dead space is advisable, while a dilution of the drug is useful with other syringes. This article derives from a nonsystematic review of the available literature, with special attention to recent international guidelines and expert recommendations, combined to authors' clinical practice in large tertiary pediatric hospitals and will provide concise and practical information for the use of low-molecular weight heparin in childhood and infancy in a sort of "answering frequently asked questions."

Vaccine effectiveness against severe laboratory-confirmed influenza in children: results of two consecutive seasons in Italy.

OBJECTIVE: To evaluate the effectiveness of seasonal influenza vaccine in preventing Emergency Department (ED) visits and hospitalisations for influenza like illness (ILI) in children. METHODS: We conducted a test negative case-control study during the 2011-2012 and 2012-2013 influenza seasons. Eleven paediatric hospital/wards in seven Italian regions participated in the study. Consecutive children visiting the ED with an ILI, as diagnosed by the doctor according to the European Centre for Disease Control case definition, were eligible for the study. Data were collected from trained pharmacists/physicians by interviewing parents during the ED visit (or hospital admission) of their children. An influenza microbiological test (RT-PCR) was carried out in all children. RESULTS: Seven-hundred and four children, from 6 months to 16 years of age, were enrolled: 262 children tested positive for one of the influenza viruses (cases) and 442 tested negative (controls). Cases were older than controls (median age 46 vs. 29 months), though with a similar prevalence of chronic conditions. Only 25 children (4%) were vaccinated in the study period. The overall age-adjusted vaccine effectiveness (VE) was 38% (95% confidence interval -52% to 75%). A higher VE was estimated for hospitalised children (53%; 95% confidence interval -45% to 85%). DISCUSSION: This study supports the effectiveness of the seasonal influenza vaccine in preventing visits to the EDs and hospitalisations for ILI in children, although the estimates were not statistically significant and with wide confidence intervals. Future systematic reviews of available data will provide more robust evidence for recommending influenza vaccination in children.

A novel balanced isotonic sodium solution vs normal saline during major surgery in children up to 36 months: a multicenter RCT.

BACKGROUND: The use of isotonic electrolytic solutions for the intraoperative fluid management in children is largely recognized, but the exact composition still needs to be defined. OBJECTIVES: The primary objective of this randomized controlled open trial was to compare the changes in chloride plasma concentration using two intraoperative isotonic fluid regimens (Sterofundin vs. normal saline, both added with 1% of glucose) in children undergoing major surgery. Secondary objectives were to compare changes in other electrolytes, renal function, and the occurrence of hypoglycemia. METHODS: Children aged between 1 and 36 months, scheduled for major surgery, were randomized to receive Sterofundin or saline during the intraoperative time. Children with preoperative electrolyte abnormalities, hemodynamic instability, and severe renal or hepatic dysfunction were excluded. The primary outcome was the Δ of Cl(-) (Δ = change in plasma concentration between post- and pre-infusion), and secondary outcomes included Δ of other electrolytes and intraoperative hypoglycemia. RESULTS: A total of 240 patients were included in the two study sites and randomized to receive Sterofundin plus 1% glucose or normal saline plus 1% glucose, in a open fashion (229 were finally analyzed). Δ of Cl- and Mg++ was statistically less relevant in patients who received intraoperative Sterofundin, and Δ of the other electrolytes was comparable between the two study groups. Relative risk of hyperchloremia was significantly higher when large volumes were infused (over than 46.7 ml·kg(-1) ), regardless of type of crystalloid infused. Hypoglycemia occurred in two of 229 patients. CONCLUSIONS: Sterofundin is safer than normal saline in protecting young children undergoing major surgery against the risk of increasing plasma chlorides and the subsequent metabolic acidosis.

Activity of linezolid and daptomycin against methicillin-resistant coagulase-negative staphylococci with increased MIC for vancomycin isolated from blood cultures in pediatric patients.

We evaluated minimal inhibitory concentration (MIC) for vancomycin, daptomycin, and linezolid in methicillin-resistant coagulase-negative staphylococci (MR-CoNS). Minimal inhibitory concentration of 2-4 mg/l for vancomycin was observed in 16% of strains, and among them 19% had MIC at breakpoint for daptomycin or linezolid. Among strains completely susceptible to vancomycin, 16% had MIC at breakpoint for daptomycin and 11% had for linezolid. This large proportion of pathogens with MIC around the breakpoint suggests a possible risk of treatment failure with these drugs. This phenomenon is worth further and constant monitoring.

Current research in empirical therapy for febrile neutropenia in cancer patients: what should be necessary and what is going on.

INTRODUCTION: Fever is an important complication in neutropenic patients and standard of care calls for empirical broad-spectrum antibiotics, followed by 'empirical' antifungal therapy in persisting fever. Emergence of infections due to resistant bacteria, especially Gram-negatives, and usefulness of empirical antifungal therapy represent the major concerns in this field. AREAS COVERED: Clinical trials registered in 5 international databases were referred for randomized clinical trials (RCTs) of empirical antibacterial therapy or empirical antifungal therapy in neutropenic cancer patients. The majority of RCTs compared antibiotics without major differences in the spectrum of activity, especially in the wake of the present epidemiology with an increase of infections and mortality due to resistant Gram-negatives; oral therapy and home care were analyzed in 3 RCTs. As regards empirical antifungal therapy, 1 ongoing study is comparing 'standard' empirical treatment vs diagnostic-driven approach. EXPERT OPINION: In an era of increasing antibiotic resistance the comparison of different strategies more than that of different drugs will probably represent the future in studies in this field. The next future will tell us if a diagnostic-driven approach is safe for fungal infections, or if we should continue to treat them only on the basis of the persistence of febrile neutropenia.

Gram-negative urinary tract infections and increasing isolation of ESBL-producing or ceftazidime-resistant strains in children: results from a single-centre survey.

Urinary tract infections (UTIs) are an important cause of morbidity in paediatrics, especially related to urinary tract malformation and neurogenic bladder dysfunction. The infection control team of Istituto Giannina Gaslini, Genova, Italy, performs a prospective survey on the epidemiology of UTI in children admitted in the hospital, and data are expressed as episodes/1000 days of hospital admission. From 2007 to 2011 there was an increase in the rate of Gram-negative UTIs, especially in the Nephrology Unit (from 11.63 to 27.48, r-coefficient 0.95, P minor 0.05), associated with an increase in infections due to ESBL-producing strains (from 0.54 to 2.55, r-coefficient 0.89, P 0.05). This study indicates that there is an increase in the rate of Gram-negative UTIs, also due to resistant strains. The cause may be multifactorial, but it is noteworthy that it has been mainly observed in a ward where low-dose, long-term administration of antibacterial prophylaxis in children with urinary malformations or neurogenic bladder dysfunction is routine. This phenomenon gives cause for concern and should be monitored carefully to avoid the risk of selecting resistant bacteria that have no therapeutic options.

Response to rituximab in 3 children with opsoclonus-myoclonus syndrome resistant to conventional treatments.

We report the 1 year follow-up of 3 children affected by non-paraneoplastic Opsoclonus-Myoclonus Syndrome (OMS) resistant to conventional therapies (steroids, ACTH and intravenous immunoglobulins) who were treated with an anti CD20 monoclonal antibody (rituximab). Treatment response was recorded on the basis of an international score at 0, 3, 6, 9 and 12 months. Despite the long disease duration and the numerous previously administered treatments, all patients underwent rapid and persistent neurological recovery following rituximab administration, thus suggesting a potential role of this drug even in pre-treated patients.