Serum Concentrations and Dietary Intake of Vitamin B12 in Children and Adolescents on Metformin: A Case-Control Study.

The International Society of Pediatric and Adolescent Diabetes (ISPAD) recommends metformin (MET) use for metabolic disturbances and hyperglycemia, either in combination with insulin therapy or alone. A caveat of MET therapy has been suggested to be biochemical vitamin B12 deficiency, as seen mainly in studies conducted in adults. In the present case-control study, children and adolescents of different weight status tiers on MET therapy for a median of 17 months formed the cases group (n = 23) and were compared with their peers not taking MET (n = 46). Anthropometry, dietary intake, and blood assays were recorded for both groups. MET group members were older, heavier, and taller compared with the controls, although BMI z-scores did not differ. In parallel, blood phosphorus and alkaline phosphatase (ALP) concentrations were lower in the MET group, whereas MCV, Δ4-androstenedione, and DHEA-S were higher. No differences were observed in the HOMA-IR, SHBG, hemoglobin, HbA1c, vitamin B12, or serum 25(OH)D3 concentrations between groups. Among those on MET, 17.4% exhibited vitamin B12 deficiency, whereas none of the controls had low vitamin B12 concentrations. Participants on MET therapy consumed less energy concerning their requirements, less vitamin B12, more carbohydrates (as a percentage of the energy intake), and fewer fats (including saturated and trans fats) compared with their peers not on MET. None of the children received oral nutrient supplements with vitamin B12. The results suggest that, in children and adolescents on MET therapy, the dietary intake of vitamin B12 is suboptimal, with the median coverage reaching 54% of the age- and sex-specific recommended daily allowance. This low dietary intake, paired with MET, may act synergistically in reducing the circulating vitamin B12 concentrations. Thus, caution is required when prescribing MET in children and adolescents, and replacement is warranted.

The Synergistic Effects of a Complementary Physiotherapeutic Scheme in the Psychological and Nutritional Treatment in a Teenage Girl with Type 1 Diabetes Mellitus, Anxiety Disorder and Anorexia Nervosa.

Type 1 diabetes mellitus (T1DM) is a chronic disease that can affect the physical and mental health of children and adolescents, often leading to anxiety disorders with chronic activation of the hypothalamic axis (HPA). Moreover, a great proportion of adolescents with T1DM also demonstrate anorexia nervosa (AN), due to the increased preoccupation with food and the need to have an acceptable body image. Herein is described the first case study of an adolescent patient diagnosed with T1DM, anxiety disorder (AD), and AN. A 14-year-old girl with T1DM since the age of 12 years presented weight loss at age 13 years and 3 months and low body mass index (BMI), which did not improve despite dietary recommendations and adequate disease control. Additionally, she presented menstrual disorders at the age of 12 years and 11 months (menstrual age 12 years and 1 month). A psychological evaluation of the teenager was conducted using a semi-structured interview that assessed perceived stress, health status, quality of life, and depression. AD and AN were diagnosed and the patient initiated an intervention focusing on psychological health and nutrition and which incorporated physiotherapeutic relaxation sessions and breathing exercises. After 3 months of treatment, the patient's BMI was increased, and a normal menstrual cycle was apparent. These results have since remained consistent. Stress leads to the appearance of AN and menstrual disorders. Therefore, physiotherapeutic programs could reduce stress and effectively ameliorate AN and AD.

Use of Ceftazidime-avibactam for the Treatment of Extensively drug-resistant or Pan drug-resistant Klebsiella pneumoniae in Neonates and Children <5 Years of Age.

BACKGROUND: Emergence of extensively drug-resistant (XDR) or pan drug-resistant (PDR) Enterobacteriaceae is a major public threat especially for young patients. Treatment options for these bacteria are extremely limited with no safety data existing for neonates and children. Ceftazidime-avibactam has activity against Gram-negative bacteria producing Klebsiella pneumoniae carbapenemase, but virtually no data exist on its use in neonatal and pediatric patients. METHODS: We present a single-center case series of neonates and children <5 years treated with ceftazidime-avibactam for XDR or PDR K. pneumoniae infections until August 2018. Medical records of patients who received ceftazidime-avibactam for at least 2 days (6 doses) were reviewed. Clinical, laboratory and microbiologic data were collected using a prestructured form. Adverse events and clinical/microbiologic responses and 15- and 30-day outcome were assessed. RESULTS: In our case series, 8 patients (median age 53 days, range from 13 days to 4.5 years) received 9 courses of ceftazidime-avibactam at a dose of 62.5 mg/kg q8h for suspected or proven XDR/PDR K. pneumoniae infections including bloodstream infections (8 courses), central nervous system infections (2 courses) and urinary tract infection (1 course). All patients were critically ill and received other antibiotics prior and concomitantly with the administration of ceftazidime-avibactam. There was no treatment discontinuation due to adverse events. Clinical and microbiologic responses occurred in all patients, and no patient died by day 30. CONCLUSIONS: Administration of ceftazidime-avibactam appears to be well tolerated and efficacious against in vitro susceptible XDR or PDR Enterobacteriaceae without being associated with significant adverse events.

In vitro combination therapy with isavuconazole against Candida spp.

Combination therapy may be an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis has not been studied. We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of isavuconazole with amphotericin B or micafungin, an echinocandin, against strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. The Bliss independence-based drug interactions modeling showed that the combination of isavuconazole and micafungin resulted in synergistic interactions against C. albicans, C. parapsilosis, and C. krusei. The degree of synergy ranged from 1.8% to 16.7% (mean %ΔΕ value) with the highest synergy occurring against C. albicans (⊙SYN% = 8.8%-110%). Time-kill assays showed that the isavuconazole-micafungin combination demonstrated concentration-depended synergy against C. albicans and C. parapsilosis. The combined interaction by Bliss analysis between isavuconazole and amphotericin B was indifferent for C. albicans, C. parapsilosis, and C. tropicalis while for C. glabrata was antagonistic (-2% to -6%) and C. krusei synergistic (3.4% to 7%). The combination of isavuconazole-amphotericin B by time-kill assay was antagonistic against C. krusei and C. glabrata. Collectively, our findings demonstrate that combinations of isavuconazole and micafungin are synergistic against Candida spp., while those of isavuconazole and amphotericin B are indifferent in vitro.

Comparison of cotrimoxazole vs. second-generation cephalosporins for prevention of urinary tract infections in children.

BACKGROUND: Antimicrobial prophylaxis is recommended for the prevention of urinary tract infections (UTI) in high-risk children. However, there is growing concern about the use of ß-lactams as prophylaxis and subsequent development of antibiotic resistance. METHODS: In this prospective, randomized, crossover controlled trial we compared cotrimoxazole (SXT) and second-generation cephalosporins (2GC) as UTI prophylaxis in children ranging in age from 1 to 60 months. Eligible patients were 1:1 randomized to receive either SXT or 2GC for the initial 6-month period (1 course), then switched to the other antimicrobial agent class for the subsequent course, with switching continuing after each course until the end of the study. Urethral orifice cultures (UOCs) were obtained at the time of switching antimicrobial prophylaxis. RESULTS: Among 97 children (mean age 13.6 months) on prophylaxis, breakthrough UTIs occurred during 13.3 % (10/75) of SXT courses and 10.3 % (8/78) of 2GC courses (p = 0.62). 2GC failed earlier than SXT (mean ± standard error: 0.81 ± 0.1 vs. 2.37 ± 0.36 months, respectively; p = 0.028). Pseudomonas aeruginosa and Enterococcus spp. were more frequently isolated after 2GC courses than after SXT courses [22.6 vs. 4.8 % (p = 0.02) and 20.7 vs. 4.8 % (p = 0.035), respectively]. Prophylaxis with 2GC significantly increased resistance to both 2GC and SXT, while SXT prophylaxis did not affect susceptibility to 2GC. CONCLUSIONS: While SXT and 2GC appear to be equally efficacious as UTI prophylaxis in children, the latter exert a broader effect on patients' flora and development of bacterial resistance, suggesting that SXT may be more appropriate for UTI prophylaxis than 2GC.

The Role of Echinocandins in Candida Biofilm-Related Vascular Catheter Infections: In Vitro and In Vivo Model Systems.

Candida biofilm-associated infections of central venous catheters are a challenging therapeutic problem. Recent in vitro and in vivo studies of the structure, formation, pathogenesis, and treatment establish a rationale for new approaches to management of these tenacious infections.

Role of Echinocandins in Fungal Biofilm-Related Disease: Vascular Catheter-Related Infections, Immunomodulation, and Mucosal Surfaces.

Biofilm-related infections have become an increasingly important clinical problem. Many of these infections occur in patients with multiple comorbidities or with impaired immunity. Echinocandins (caspofungin, micafungin, and anidulafungin) exert their fungicidal activity by inhibition of the synthesis of the (1→3)-ß-d-glucan. They are active among in vitro and in vivo model systems against a number of Candida species and filamentous fungi in their planktonic and biofilm phenotype. Their superior activity against biofilms poses them in an advantageous position among the antifungal armamentarium. However, additional studies are warranted to expand our knowledge on the role of echinocandins against biofilm-related infections.

Current management of late onset neonatal bacterial sepsis in five European countries.

UNLABELLED: Late onset neonatal sepsis (LOS) has a high mortality and the optimal management is poorly defined. We aimed to evaluate new expert panel-derived criteria to define LOS and characterize the current management and antibiotic susceptibility of LOS-causing organisms in Europe. A prospective observational study enrolled infants aged 4 to 90 days in five European countries. Clinical and laboratory findings as well as empiric treatment were recorded and patients were followed until the end of antibiotic therapy. Failure was defined as a change of primary antibiotic, no resolution of clinical signs, appearance of new signs/pathogens or death. Antibiotic therapy was considered appropriate if the organism was susceptible to at least one empiric antibiotic. 113 infants (median age 14 days, 62 % ≤1500 g) were recruited; 61 % were culture proven cases (28 CoNS, 24 Enterobacteriaceae, 11 other Gram-positives and 6 Gram-negative non-fermentative organisms). The predictive value of the expert-panel criteria to identify patients with a culture proven LOS was 61 % (95 % CI 52 % to 70 %). Around one third of Enterobacteriaceae were resistant to ampicillin + or cefotaxime + gentamicin but only 10 % to meropenem. Empiric treatment contained a total of 43 different antibiotic regimens. All-cause mortality was 8 % with an additional 45 % classified as failure of empiric therapy, mainly due to change of primary antibiotics (42/60). CONCLUSIONS: The expert panel-derived diagnostic criteria performed well identifying a high rate of culture proven sepsis. Current management of LOS in Europe is extremely variable suggesting an urgent need of evidence-based guidelines.

Differential correlation between rates of antimicrobial drug consumption and prevalence of antimicrobial resistance in a tertiary care hospital in Greece.

OBJECTIVE: To investigate whether there is a correlation between the rates of antimicrobial drug consumption in hospital departments and the prevalence of antimicrobial resistance among clinically important bacteria recovered in the hospital. DESIGN: Retrospective study. SETTING: Tertiary care hospital in Greece. METHODS: Data on antimicrobial consumption (from January 2001 through December 2004) were expressed as defined daily doses per 100 bed-days. The prevalence of antimicrobial resistance among isolates of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterococcus faecium recovered during the same time period were calculated by the microbiology department. We then performed the following analyses: (1) a comparison of the consumption rates for different antimicrobial groups in individual hospital departments, (2) a comparison of the prevalence of resistance to different antimicrobials, and (3) a correlation analysis of antimicrobial consumption rates and the prevalence of antimicrobial resistance. RESULTS: The rates of antimicrobial consumption and the prevalence of resistance varied substantially among the hospital's departments. The annual rate of consumption for carbapenems correlated with the rate of consumption for glycopeptides and third-generation cephalosporins (P < .05). Among P. aeruginosa isolates, the prevalence of imipenem resistance correlated with the prevalence of resistance to amikacin, ciprofloxacin, and ceftazidime (P < .05). The rate of carbapenem consumption correlated with the prevalence of imipenem resistance among P. aeruginosa and A. baumannii isolates (P < .05). The rate of aminoglycoside consumption correlated with the prevalence of amikacin resistance among P. aeruginosa, K. pneumoniae, and E. coli isolates (P < .05). However, the rate of consumption for fluoroquinolones and glycopeptides had no correlation with the prevalence of ciprofloxacin resistance among gram-negative bacteria or vancomycin resistance among E. faecium isolates. CONCLUSIONS: These data are suggestive of a differential relationship between antimicrobial consumption and the prevalence of antimicrobial resistance among various species and for various antimicrobial agents. These findings may help to optimize antimicrobial prescription policies in the hospital, especially in departments that have both high rates of antimicrobial consumption and a high prevalence of antimicrobial resistance.

Infections caused by Scedosporium spp.

Scedosporium spp. are increasingly recognized as causes of resistant life-threatening infections in immunocompromised patients. Scedosporium spp. also cause a wide spectrum of conditions, including mycetoma, saprobic involvement and colonization of the airways, sinopulmonary infections, extrapulmonary localized infections, and disseminated infections. Invasive scedosporium infections are also associated with central nervous infection following near-drowning accidents. The most common sites of infection are the lungs, sinuses, bones, joints, eyes, and brain. Scedosporium apiospermum and Scedosporium prolificans are the two principal medically important species of this genus. Pseudallescheria boydii, the teleomorph of S. apiospermum, is recognized by the presence of cleistothecia. Recent advances in molecular taxonomy have advanced the understanding of the genus Scedosporium and have demonstrated a wider range of species than heretofore recognized. Studies of the pathogenesis of and immune response to Scedosporium spp. underscore the importance of innate host defenses in protection against these organisms. Microbiological diagnosis of Scedosporium spp. currently depends upon culture and morphological characterization. Molecular tools for clinical microbiological detection of Scedosporium spp. are currently investigational. Infections caused by S. apiospermum and P. boydii in patients and animals may respond to antifungal triazoles. By comparison, infections caused by S. prolificans seldom respond to medical therapy alone. Surgery and reversal of immunosuppression may be the only effective therapeutic options for infections caused by S. prolificans.

Micafungin: pharmacology, experimental therapeutics and clinical applications.

Invasive fungal infections are important causes of morbidity and mortality in hospitalised patients. Current therapy with amphotericin B and antifungal triazoles has overlapping targets and is limited by toxicity and resistance. Echinocandins are a new class of antifungal drugs, which inhibit the synthesis of 1,3-beta-D-glucan. This homopolysaccharide is an important component of the cell wall of many pathogenic fungi, providing osmotic stability and functioning in cell growth and cell division. Micafungin, which is a member of the echinocandin class, exhibits in vitro fungicidal or fungistatic activity against a variety of fungal pathogens which include Candida and Aspergillus species but not Cryptococcus, Fusarium or Zygomycetes. Micafungin demonstrates linear pharmacokinetics, which are not altered by drugs metabolised through the P450 enzyme system. The preclinical and clinical data strongly support the development of micafungin for treatment of proven or suspected mucosal and invasive Candida infections in immunocompetent and immunocompromised patients. This paper reviews the preclinical and clinical pharmacology of micafungin and its potential role for treatment of fungal invasive infections in patients.