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Introduction : Pharmacometabolomics is an emerging science pursuing the application of precision medicine. Combining both genetic and environmental factors, the so-called pharmacometabolomic approach guides patient selection and stratification in clinical trials and optimizes personalized drug dosage, improving efficacy and safety. Areas covered : This review illustrates the progressive introduction of pharmacometabolomics as an innovative solution for enhancing the discovery of novel drugs and improving research and development (R&D) productivity of the pharmaceutical industry. An extended analysis on published pharmacometabolomics studies both in animal models and humans includes results obtained in several areas such as hepatology, gastroenterology, nephrology, neuropsychiatry, oncology, drug addiction, embryonic cells, neonatology, and microbiomics. Expert opinion : a tailored, individualized therapy based on the optimization of pharmacokinetics and pharmacodynamics, the improvement of drug efficacy, and the abolition of drug toxicity and adverse drug reactions is a key issue in precision medicine. Genetics alone has become insufficient for deciphring intra- and inter-individual variations in drug-response, since they originate both from genetic and environmental factors, including human microbiota composition. The association between pharmacogenomics and pharmacometabolomics may be considered the new strategy for an in-deep knowledge on changes and alterations in human and microbial metabolic pathways due to the action of a drug.

Introduction: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders consisting of delayed or impaired language development and difficulties in social interactions. The very high degree of phenotypic heterogeneity in ASD originates from the interaction between environmental risk factors and susceptible genetic loci, leading to epigenetic DNA methylation. Advances in system biology are becoming strategic for implementing knowledge on the ASD aetiology and for the early diagnosis of the disease after birth., Areas Covered: We overhauled the value of either targeted or untargeted metabolomics studies in autism for identifying the most relevant metabolic pathways and key metabolites implicated in the disease, with special emphasis to mammalian-microbial metabolites. The most discriminant metabolites in ASD belong to amino acid metabolism, antioxidant status, nicotinic acid metabolism, and mitochondrial metabolism. Expert commentary: Most published studies point out the role of metabolites derived from the gut microbiota: they can modulate the behavioral phenotype of the autistic children, greatly influencing host metabolic pathways and the immune system, shaping the individual susceptibility to the disease. Pitfalls and caveats in metabolomics results across studies have been additionally recognized and discussed leading to the conclusion that metabolomics studies in ASD are far to be definitive and univocal.

Metabolomics, the latest of omics disciplines, has been successfully used in various fields of basic research such as pharmacology and toxicology. Recently, this new science has gained an important role in the translational research of diagnostics. In this regard, the challenge for neonatologists and medical laboratories is to diagnose neonatal sepsis, a disease with high mortality and morbidity due to the difficulty in diagnosing it. Metabolomics, through its ability to identify perturbations caused by this condition, aims at recognizing metabolites that characterize neonatal sepsis with high specificity and sensitivity. The purpose of this review is to highlight the ability of metabolomics to find early biomarkers for this condition, as well as to predict the toxic effects caused by antibiotics.

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a leading pathogen causing nosocomial infections. Many studies have shown that the restricted use of antibacterials is associated with a decline in resistance. To establish whether an intervention protocol designed to limit the use of cephalosporins can lower mRSA infection rates and impact on Gram-negative bacteria susceptibility in an intensive Care Unit (ICU), we conducted a prospective, non-randomized, before-after intervention study in an 18-bed ICU in Genoa, Italy. The intervention was a hospital antibiotic control policy and the observation was routine monitoring for nosocomial infections and antibiotic use, recording periodically the incidence density and MRSA prevalence. The intervention included a new antibiotic guideline that restricted the use of cephalosporins for all ICU inpatients. The analysis showed that the intervention determined a significant reduction in cephalosporin usage (-70.3%), while fluoroquinolones, mainly ciprofloxacin, increased after introduction of the antibiotic policy (+46.5%). A significant reduction in the percentage of MRSA infections (-30%) and heterogeneous susceptibility patterns in Klebsiella pneumoniae and Pseudomonas aeruginosa were noted.

Procalcitonin (PCT) is the precursor of calcitonin, normally synthesized in the C-cells of the thyroid gland. Systemic inflammation and sepsis induce PCT production by various cell types, including hepatocytes, nephrons, monocytes. PCT begins to rise four hours after exposure to bacterial endotoxins, peaking at six to eight hours, and remaining raised for at least 24 hours with a half-life of 25-30 hours. Serum PCT levels significantly increase in systemic bacterial infection, necrotizing enterocolitis, and during both early and late onset neonatal sepsis. By using a cut-off limit of 0,5 microg/L, the PCT positive likelihoud ratio was found of 12.5. PCT has a theoretical advantage as a marker of systemic induction in sepsis and its half-life suitable for daily monitoring of disease progress. PCT may be useful in assessing the severity of infection, following the progress of treatment, and predicting outcomes.

A proper dosing regimen is fundamental when antibiotics with a low therapeutic index, as aminoglycosides (AMG), are used. AMG pharmacokinetics present a strong interindividual and intraindividual variability in neonates; in the premature neonate AMG clearance is reduced and the half-life is longer, leading to higher serum trough concentrations. Neonates may require therapeutic drug monitoring (TDM) and a "tailored" therapeutic regimen. The aim of this work is to present our personal experience wtih TDM of gentamicin in 68 newborns and to compare it with data available in the literature.

Early diagnosis and treatment of neonatal sepsis are essential to prevent severe and life threatening complications. Consequently, rapid diagnostic tests capable to differentiate infected from non-infected newborns have the potential to make a significant impact on neonatal care. A new real-time polymerase chain reaction (PCR; LightCycler SeptiFast test M GRADE) has been proposed in the routine assessment of neonatal sepsis for the detection and identification of bacterial and fungal DNA from microorganisms which cause approximately 90% of all blood stream infections. The LightCycler SeptiFast test can detect and identify simultaneously the 25 most important bacterial and fungal species causing bloodstream infections within few hours by using a small volume of a single whole blood sample. Real-time PCR can be easily incorporated into the hospital setting for term or near-term infants admitted to the neonatal intensive care unit for sepsis evaluation.

The study aim was to evaluate urinary excretion of Retinol Binding Protein (RBP), compared with urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), in preterm infants with anoxia and netilmicin treatment. Urinary RBP and NAG were evaluated in 83 preterm newborns divided in 4 groups: 37 healthy preterm newborns (controls); 14 with neonatal anoxia; 16 treated with ampicillin + netilmicin; 16 with neonatal anoxia and treated with ampicillin + netilmicin. RBP was determined by an automated nephelometric technique and NAG by a colorimetric method on 5-h urine samples in the first week of life. Results showed that urinary excretion of RBP (average from first week values) was 1.06+/-0.67 g/mol creatinine (mean +/- SD) in controls, 1.99+/-1.41 in antibiotic-treated newborns, 3.99+/-4.57 in anoxic newborns and 3.75+/-3.48 in anoxic newborns under antibiotic treatment. When gestational age was not considered, a marked effect of anoxia (P<0.001) and a borderline effect of netilmicin (P<0.059) on RBP excretion were detected by ANOVA. However when gestational age was also considered by analysis of covariance, it appeared as the strongest predictor of RBP excretion (P<0.001), while the effect of netilmicin was no longer significant (P=0.181). The effect of anoxia persisted, although less remarkable (P=0.010). Conversely anoxia did not affect urinary NAG excretion, which was rather correlated with gestational age and netilmicin administration. The authors conclude that RBP and NAG urinary excretion may be used to discriminate between neonatal anoxia and netilmicin treatment, respectively as etiologic factors of renal tubular damage in the newborn.

The literature does not contain reports regarding teicoplanin overdose in newborns. In a neonate with a history of recent postasphyctic acute renal failure which recovered within 7 days of life, antibiotic therapy with teicoplanin was started for sepsis due to Staphylococcus hominis. However, for 5 days the dosage was excessive (20 mg/kg twice daily instead of an initial dose of 16 mg/kg and then doses of 8 mg/kg once daily). Once this error had been noted, therapy was immediately suspended. Clinically the newborn had improved and blood culture at the end of the therapy was negative. Biohumoral tests revealed constantly normal levels of serum creatinine, serum cystatin C and blood nitrogen. Urinary parameters of tubulotoxicity were also within normal values. Urinary epidermal growth factor was increased. Teicoplanin was well tolerated at the renal level in the newborn even in this case of excessive dosage.