Limited Sampling Strategies to Predict Ganciclovir Exposure after Valganciclovir Administration and to Reduce Monitoring Constraints in Renal Transplant Children.

Valganciclovir, the ganciclovir prodrug, is an antiviral agent used to prevent cytomegalovirus infection in renal transplant children. Therapeutic drug monitoring is still necessary to ensure optimal therapeutic area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 60 µg·h/mL since valganciclovir presents a high pharmacokinetic variability. To calculate ganciclovir AUC0-24 with the trapezoidal method, 7 samples are needed. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy (LSS) for individualizing valganciclovir dose in renal transplant children. Rich pharmacokinetic data from ganciclovir plasmatic dosages measured in renal transplant children who received valganciclovir to prevent cytomegalovirus infection at Robert Debré University Hospital were collected retrospectively. Ganciclovir AUC0-24s were calculated using the trapezoidal method. The LSS was developed using a multilinear regression approach to predict AUC0-24. The patients included were divided into two groups for model development (50 patients) and validation (30 patients). A total of 80 patients were included between February 2005 and November 2018. Multilinear regression models were developed on 50 pharmacokinetic profiles (50 patients) and validated with an independent group of 43 pharmacokinetic profiles (30 patients). Regressions based on samples collected at T1h-T4h-T8h, T2h-T4h-T8h, or T1h-T2h-T8h presented the best AUC0-24 predictive performances with an average difference between reference and predicted AUC0-24 of -0.27, 0.34, and -0.40 µg·h/mL, respectively. In conclusion, valganciclovir dosage adaptation was required in children to achieve the target AUC0-24. Three LSS models using three pharmacokinetic blood samples instead of seven will be useful for individualizing valganciclovir prophylaxis in renal transplant children.

Population pharmacokinetics of ceftazidime in critically ill children: impact of cystic fibrosis.

BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens. METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.

[Improvement of antibiotic therapy adequacy with local guidelines and their reassessment through a multidisciplinary action: Prospective study in an Internal Medicine department]. / Amélioration de l'adéquation des antibiothérapies aux recommandations et de leur réévaluation par une action pluridisciplinaire : étude prospective dans un service de médecine interne.

INTRODUCTION: The implementation of antimicrobial stewardship actions is important in the fight against antimicrobial resistance. The objective of our study was to evaluate the impact of a multidisciplinary program on the adequacy of antibiotic prescriptions with local guidelines in terms of indication, molecule, dosage and treatment duration during the 48-72h reassessment in an internal medicine department. METHOD: This was a before/after monocentric, prospective study. All patients hospitalized in the internal medicine department who were treated with antibiotics for at least 48h were included. The intervention had two components: training of residents about antibiotic treatment and development of a multidisciplinary 48-72h reassessment team. Our primary endpoint was the adequacy of prescriptions with local guidelines, assessed by an independent blinded committee. We also measured antibiotic consumptions. RESULTS: One hundred and twelve patients were included. Adequacy with local recommendations increased from 57.1% to 97.8% (P<0.01), including for the duration of treatment. Traceability of reassessment in medical records increased from 65.3 % to 97.8 % (P<0.01). Finally, the part of consumption of antibiotics with high risk of resistance selection decreased during the period "after" (-10.2 %, P<0.01). CONCLUSION: The set-up of a multimodal (association of pedagogic and incentive actions) and multidisciplinary (internist, clinical pharmacist and antimicrobial stewards) action improved the adequacy of antibiotic prescriptions with local guidelines.

Population pharmacokinetics of ganciclovir after valganciclovir in renal transplant children.

BACKGROUND: Valganciclovir, the ganciclovir prodrug, is an antiviral agent administered orally to prevent or treat cytomegalovirus infection in solid organ transplant recipients. Dosing regimen of valganciclovir is still controversial in children, as the number of patients reaching the Area Under the Curve at steady state (AUCss) target (40 - 60 mg.h/L) remains highly variable. The aim of this study was to determine the population pharmacokinetics of valganciclovir in paediatric renal transplant recipients and propose an appropriate dosing regimen. METHODS: Renal transplant children who received valganciclovir to prevent or treat cytomegalovirus infection at Robert Debré University Hospital were included. Plasma ganciclovir concentrations were determined by high performance liquid chromatography and ultraviolet detection. Population pharmacokinetic analysis was performed with NONMEM software. RESULTS: 104 patients, aged 2 to 20 years, treated with valganciclovir administered at a mean dose of 17.3 ± 6.1 mg/kg to prevent and/or treat cytomegalovirus infection after renal transplantation were included. A total of 1212 samples were available. A two-compartment model with first-order elimination best fitted the data: ganciclovir clearance increased with body surface area, was 15% higher in boys and decreased with increasing creatinine concentration. Central volume of distribution increased with body surface area and was 14% higher in boys. According to the personalized dosing regimen, 65.7% and 65.4% of children were predicted to achieve the AUCss target for cytomegalovirus prophylaxis and treatment, respectively. CONCLUSION: A new pharmacokinetic model was built allowing to propose individualised dose adapted to renal transplanted paediatric patients characteristics.

Variability of ciprofloxacin pharmacokinetics in children: impact on dose range in sickle cell patients.

Objectives: To determine the ciprofloxacin population pharmacokinetics in paediatric patients and the impact of underlying disease and evaluate the appropriateness of current dosage regimens. Patients and methods: Plasma concentrations of ciprofloxacin from children treated with ciprofloxacin were measured by HPLC. The pharmacokinetic population analysis was performed using NONMEM v7.2 (Icon Development Solutions, USA). Results: Two datasets were combined and 128 plasma concentrations in 60 patients aged 5.6 years (range 0.3-18.9), treated with a median daily dose of 30.0 mg/kg (range 6.5-52.0) presenting with sickle cell disease (SCD; n = 20, 33%), haemopathy (n = 15, 25%), cystic fibrosis (CF; n = 3, 5%) and other diseases (n  =  22, 37%) were analysed. Data were best described by a two-compartment model with first-order elimination. Ciprofloxacin clearance (mean ±â€Šâ€ŠSD) was 0.81 ±â€Š0.30 L/h/kg, increased allometrically with weight, decreased with increasing creatinine concentration, was 89% higher in SCD compared with non-SCD patients and increased by 0.95 L/h/kg per year of age. The volume of distribution was 6.9 L/kg and depended only on the weight. Monte Carlo simulations were performed separately in SCD and non-SCD patients to target an AUC/MIC ratio >125 at steady-state, required for antibacterial efficacy, and recommendations of dosing regimens were proposed. Conclusions: In addition to known covariates, ciprofloxacin clearance is greater in SCD children compared with non-SCD patients. The dosing of this agent needs to be adapted to this subgroup of patients.

Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.

Morquio A (Mucopolysaccharidosis IVA; MPS IVA) is an autosomal recessive lysosomal storage disorder caused by partial or total deficiency of the enzyme galactosamine-6-sulfate sulfatase (GALNS; also known as N-acetylgalactosamine-6-sulfate sulfatase) encoded by the GALNS gene. Patients who inherit two mutated GALNS gene alleles have a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing GAG accumulation within lysosomes and consequently pleiotropic disease. GALNS mutations occur throughout the gene and many mutations are identified only in single patients or families, causing difficulties both in mutation detection and interpretation. In this study, molecular analysis of 163 patients with Morquio A identified 99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function, of which 39 are previously unpublished, together with 26 single-nucleotide polymorphisms. Recommendations for the molecular testing of patients, clear reporting of sequence findings, and interpretation of sequencing data are provided.

Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients.

In this study, 103 unrelated South-American patients with mucopolysaccharidosis type II (MPS II) were investigated aiming at the identification of iduronate-2-sulfatase (IDS) disease causing mutations and the possibility of some insights on the genotype-phenotype correlation The strategy used for genotyping involved the identification of the previously reported inversion/disruption of the IDS gene by PCR and screening for other mutations by PCR/SSCP. The exons with altered mobility on SSCP were sequenced, as well as all the exons of patients with no SSCP alteration. By using this strategy, we were able to find the pathogenic mutation in all patients. Alterations such as inversion/disruption and partial/total deletions of the IDS gene were found in 20/103 (19%) patients. Small insertions/deletions/indels (<22 bp) and point mutations were identified in 83/103 (88%) patients, including 30 novel mutations; except for a higher frequency of small duplications in relation to small deletions, the frequencies of major and minor alterations found in our sample are in accordance with those described in the literature.

Avaliação in vitro da eficácia de extratos de plantas medicinais do Cerrado frente Staphylococcus aureus isolado de diferentes fontes de propriedades leiteiras / In-vitro evaluation of extract of medicinal plants from Cerrado against the Staphylococcus aureus isolated from different origins on dairy farms

O presente estudo teve como objetivo avaliar o potencial de atividade antimicrobiana in vitro dos extratos de algumas plantas endêmicas do Cerrado tais como Baccharis dracunculifolia. Cochlospermum regium. Croton antisyphiliticus. Eugenia dysenterica e Lippia sidoides, frente ao agente Staphylococcus aureus isolado de leite mastítico, ósteo do teto da vaca, equipamento de ordenhadeira, fossas nasais e garganta do ordenhador. Os extratos foram preparados a partir das partes aéreas e sistema radicular das plantas utilizando os solventes metanol, hexano e clorofórmio na concentração de 10%. Para avaliação da atividade antimicrobiana foi aplicada a técnica de microdiluição em caldo para determinação da Concentração Inibitória Mínima (CIM) seguida da determinação da Concentração Bactericida Mínima (MBC). Os extratos de Baccharis dracunculifolia. Croton antisyphiliticus, seguido do extrato de Lippia sidoides, apresentaram, respectivamente, melhor atividade inibitória sobre a multiplicação da bactéria Staphylococcus aureus. Os resultados obtidos demonstraram, ainda, que as estirpes isoladas do leite e das fossas nasais do ordenhador foram resistentes a gentamicina, princípio ativo muito utilizado no combate à mastite bovina, porém sensíveis aos extratos das plantas referidas, reforçando a importância das plantas medicinais como recurso terapêutico e sua aplicabilidade.

The objective of this study is to evaluate the potencial microbial activity in-vitro from the extract of some endemic plants from Cerrado such as Baccharis dracunculifolia. Cochlospermum regium. Croton antisyphiliticus. Eugenia dysenterica and Lippia sidoides, against the agent Staphylococcus aureus isolated from bovine mastitic milk, osteo from cow's teat, milker equipament, nasal cavitites and milker's gullet. The extracts were prepared from aerial parts as well as the reticular systems of plants using the solvents methanol, hexane and chloroform at a concentration of 10%. To evaluate the antimicrobial activity, the technique of microdilution in broth was used for determining the Minimal Inibitory Concentration (MIC) followed by the determination of Minimal Bactericidal Concentration (MBC). The extracts from Baccharis dracunculifolia and Croton antisyphiliticus, followed by extracts from Lippia sidoides, reported respectively, presented better inhibitory activity against the multiplication of the bacteria Staphylococcus aureus. Furthermore, the results demonstrate that the isolated strains from the milk and nasal cavities of the milker showed strong resistance against gentamicin, active agent commonly applied to combat mastitis bovine. However, there was sensitivity against extracts from the reported plants, reinforcing the importance of the medicinal plants as a therapeutic resource and its aplicability.

[Environmental lead poisoning from lead-glazed earthenware used for storing drinks]. / Intoxication environnementale par le plomb liée à la consommation de boisson conservée dans une cruche artisanale en céramique vernissée.

INTRODUCTION: Current unusual environmental sources of lead exposure mainly include traditional medicines, either ayurvedic remedies or others, traditional cosmetics (kohl, surma), and the use of traditional earthenware, for storage or cooking. CASE REPORTS: We report two cases of lead poisoning in adults initially identified by paroxysmal abdominal pain or anemia. In both cases, the environmental investigation evidenced one main source of lead exposure, namely a lead-glazed earthenware jug in which a drink was stored, "kefir" in the first case, and "kombucha" tea in the second one. CONCLUSION: It is recommended to search for lead intoxication in patients with unexplained anemia. Environmental sources of lead can be multiple. Their relative importance has to be ranked during the environmental investigation and among these, lead-glazed earthenware must be considered as a source of high lead exposure when drinks are stored inside and thus can soak.

Assessment of the DQB1-DQA1 complete genotype allows best prediction for IDDM.

OBJECTIVE: To analyze the HLA-DQ (human leukocyte antigen) genetic association with insulin-dependent diabetes mellitus (IDDM) patients of the Northeast Italian population. RESEARCH DESIGN AND METHODS: Fifty-one IDDM patients and 52 healthy control subjects were molecularly typed for DQB1 and DQA1 loci by using allele-specific oligonucleotide probes and polymerase chain reaction amplified genomic DNA. DNA enzyme immunoassay was used to assess allele specificities. RESULTS: IDDM status strongly correlated with DQB1 alleles carrying a non-aspartic acid (non-Asp) residue in position 57 of DQ beta-chain and DQA1 alleles with an arginine (Arg) residue in position 52 of DQ alpha-chain. Individuals with two DQB1 (non-Asp) alleles and two DQA1(Arg) alleles had the highest relative risk for disease: they constituted approximately 40% of IDDM patients compared with 0% of control subjects. Heterozygosis at either residue 57 of DQB1 or residue 52 of DQA1 was sufficient to abrogate statistical significance for disease association, although 47% of IDDM patients were included in these two groups compared with 21% of normal control subjects. On the other hand, the presence of two DQB1 alleles with Asp in position 57 was sufficient to confer resistance to disease irrespective of the DQA1 genotype. CONCLUSIONS: The results demonstrate that the complete HLA-DQ genotype, more than a single DQB1 or DQA1 locus, should be determined to estimate the highest risk for disease. Screening a population for preventive purposes and/or early signs of IDDM should then take advantage of this result, and "susceptible homozygous" individuals should be followed very closely and considered the first group of choice for possible new therapeutic trials.

[A comparative experimental study on the bonding resistance to horizontal traction under progressive loading between a self-polymerizing composite (Right-On) and a photopolymerizing composite (Transbond)]. / Studio sperimentale comparativo sulla resistenza di legame alla trazione orizzontale a carico progressivo tra un composito autopolimerizzante (Right-On) e un composito fotopolimerizzabile (Transbond).

The paper examines the bond resistance between the orthodontic clamp and tooth enamel using two different compounds: an autopolymerizing type (Right-On), already widely used in orthodontal practice, and a photopolymerizing type (Transbond) which has been recently introduced into the market. The bond was tested by applying horizontal traction with a progressively increasing weight. The results obtained were compared for statistical significance (Student's t test).

[The creation of a functional obturator plate by a direct method in the neonatal orthodontic treatment of cheilopalatoschisis]. / Realizzazione di una placca otturatrice funzionale con un metodo diretto nel trattamento ortopedico neonatale delle labio-palatoschisi.

The paper describes a simple direct method for the preparation of a functional filling plate in the neonatal orthopedic treatment of cleft palate harelip. This method allows the corrective plate to be realised so as to reproduce the complex deformed anatomical structure in the smallest detail, thus avoiding the major problems of acceptance, function and load distribution on the delicate neonatal mucosa.