The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free Mg2+ levels. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg2+ causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8+ T cells and impairs cytolytic responses against EBV. Remarkably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg2+ and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg2+ in eukaryotic cells.

Uncomplicated urinary tract infections are among the most frequently occurring infections in the United States, resulting in an estimated 8 million office visits and 1 million hospital admissions each year.1-3 Between 40% and 50% of women have reported having at least one urinary tract infection in their lives. 4Urinary tract infections can be classified by anatomic site of involvement into lower and upper urinary tract infections. Infections of the lower urinary tract include cystitis, urethritis, prostatitis, and epididymitis, and those of the upper urinary tract include pyelonephritis. Urinary tract infections may be further classified as complicated or uncomplicated. In women with a structurally and functionally normal urinary tract, cystitis and pyelonephritis are considered uncomplicated urinary tract infections. Urinary tract infections in men, elderly people, pregnant women, or patients who have an indwelling catheter or an anatomic or functional abnormality are considered complicated urinary tract infections. In this article, we outline the pharmacologic approach to the prevention and treatment of uncomplicated cystitis. ETIOLOGYRisk factors for urinary tract infections in women include frequent sexual intercourse, lack of urination after intercourse, use of a diaphragm, use of a spermicide, and a history of recurrent urinary tract infections.5,6 Although the long-term adverse effects associated with uncomplicated urinary tract infections appear to be minimal, if left untreated, urinary tract infections can interfere with daily living. As many as 80% of uncomplicated urinary tract infections are caused by Escherichia coli, followed by Staphylococcus saprophyticus in as many as 5% to 15% of cases. Enterococci, Klebsiella species and Proteus mirabilis account for a small percentage of overall infections. 7 OVERVIEW OF ANTIBIOTICSThe antimicrobial agents most commonly used to treat uncomplicated urinary tract infections include the combination drug trimethoprim and sulfamethoxazole, trimethoprim, ␤-lactams, fluoroquinolones, nitrofurantoin, and fosfomycin tromethamine. These agents are used primarily because of their tolerability, spectrum of activity against suspected uropathogens, and favorable pharmacokinetic profiles.8 In the treatment of urinary tract infections, the resolution of bacteriuria has been correlated with the concentration of the antimicrobial agent in the urine rather than serum levels.9 All the antimicrobial agents approved for the treatment of urinary tract infections achieve inhibitory urinary concentrations that significantly exceed serum levels. Also, agents such as trimethoprimsulfamethoxazole or the fluoroquinolones that eradicate aerobic gram-negative flora but have little effect on the vaginal and fecal anaerobic flora seem to provide the best long-term cures for uncomplicated urinary tract infections. 8 Resistance to antibioticsBecause most uncomplicated urinary tract infections are treated empirically, it is important for clinicians to recognize resistance patterns of uropathog...

Summary What is known and objective Despite the known significant drug-drug interaction between isavuconazole and tacrolimus there are no recommendations on dose-adjustment when these drugs are given concomitantly. We report on a patient with a mediastial Aspergillus fumigatus infection resistant to posaconazole and describe how she was successfully managed with isavuconazole therapeutic drug-level monitoring. Case description Our patient presented with a mediastial Aspergillus fumigatus infection, two years after lung transplantation. A. fumigatus was resistant to posaconazole and the patient had intolerance to voriconazole shown by elevated transaminases. The patient was given isavuconazole with drug-level monitoring. She was managed successfully with no adverse event. Tacrolimus concentration continued to increase after more than 2 weeks of therapy, and required a further reduction to 72% of the usual dose to maintain the target concentrations over a 8 week period. What is new and Conclusion When isavuconazole is given to patients on tacrolimus, the dose of the latter will need considerable reduction. We would suggest an initial 50% reduction and recommend close weekly monitoring of tacrolimus concentration. Further dose decreases of 25–50% may be required

Patients with deficiency in the interferon gamma receptor (IFN-γR) are unable to respond properly to IFN-γ and develop severe infections with nontuberculous mycobacteria (NTM). IFN-γ and IFN-α are known to signal through STAT1 and activate many downstream effector genes in common. Therefore, we added IFN-α for treatment of patients with disseminated mycobacterial disease in an effort to complement their IFN-γ signaling defect. We treated four patients with IFN-γR deficiency with adjunctive IFN-α therapy in addition to best available antimicrobial therapy, with or without IFN-γ, depending on the defect. During IFN-α treatment, ex vivo induction of IFN target genes was detected. In addition, IFN-α driven gene expression in patients’ cells and mycobacteria induced cytokine response were observed in vitro. Clinical responses varied in these patients. IFN-α therapy was associated with either improvement or stabilization of disease. In no case was disease exacerbated. In patients with profoundly impaired IFN-γ signaling who have refractory infections, IFN-α may have adjunctive anti-mycobacterial effects.

What is Known and Objective Posaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and molds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in pediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD). Methods This retrospective single-center study reviewed pediatric patients younger than 13 years of age initiated on posaconazole oral suspension. Patients were included if they were initiated on posaconazole for prophylaxis or treatment of fungal infections from September 2006 through March 2013 with at least one trough concentration collected after at least 7 days of therapy. Results and Discussion A total of 20 male patients were included, of whom 15 (75%) had chronic granulomatous disease. The median age of patients was 6.5 years (range: 2.8 – 10.7). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n=8) or treatment (n=12). Posaconazole dose referenced to total body weight ranged from 10.0 – 49.2 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (<50 ng/mL) up to 3620 ng/mL and were ≥500, ≥700, and ≥1250 ng/mL in 95, 60, and 25% of patients, respectively. What is New and Conclusions Patients younger than 13 years of age had highly variable trough concentrations and recommendations for the appropriate dosing of posaconazole oral suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure.