Quantification of Fluoroquinolone Uptake through the Outer Membrane Channel OmpF of Escherichia coli.

Decreased drug accumulation is a common cause of antibiotic resistance in microorganisms. However, there are few reliable general techniques capable of quantifying drug uptake through bacterial membranes. We present a semiquantitative optofluidic assay for studying the uptake of autofluorescent drug molecules in single liposomes. We studied the effect of the Escherichia coli outer membrane channel OmpF on the accumulation of the fluoroquinolone antibiotic, norfloxacin, in proteoliposomes. Measurements were performed at pH 5 and pH 7, corresponding to two different charge states of norfloxacin that bacteria are likely to encounter in the human gastrointestinal tract. At both pH values, the porins significantly enhance drug permeation across the proteoliposome membranes. At pH 5, where norfloxacin permeability across pure phospholipid membranes is low, the porins increase drug permeability by 50-fold on average. We estimate a flux of about 10 norfloxacin molecules per second per OmpF trimer in the presence of a 1 mM concentration gradient of norfloxacin. We also performed single channel electrophysiology measurements and found that the application of transmembrane voltages causes an electric field driven uptake in addition to concentration driven diffusion. We use our results to propose a physical mechanism for the pH mediated change in bacterial susceptibility to fluoroquinolone antibiotics.

Drug delivery from a solid formulation during breastfeeding-A feasibility study with mothers and infants.

BACKGROUND: Breastfeeding is critical to health outcomes, particularly in low-resource settings where there is little access to clean water. For infants in their first twelve months of life, the delivery of medications is challenging, and use of oral syringes to deliver liquid formulations can pose both practical and emotional challenges. OBJECTIVE: To explore the potential to deliver medicine to infants via a solid formulation during breastfeeding. METHODS: Single center feasibility study within a tertiary level neonatal unit in the UK, involving twenty-six breastfeeding mother-infant dyads. A solid formulation of Vitamin B12 was delivered to infants during breastfeeding. Outcomes included the quantitative change in serum vitamin B12 and assessment of maternal expectations and experiences. RESULTS: Delivery of Vitamin B12 through a solid formulation that dissolved in human milk did not impair breastfeeding, and Vitamin B12 levels rose in all infants from a mean baseline (range) 533 pg/mL (236-925 pg/mL) to 1871 pg/mL (610-4981 pg/mL) at 6-8 hours post-delivery. Mothers described the surprising ease of 'drug' delivery, with 85% reporting a preference over the use of syringes. CONCLUSIONS: Solid drug formulations can be delivered during breastfeeding and were preferred by mothers over the delivery of liquid formulations via a syringe.

Iron delivery from liquid-core hydrogels within a therapeutic nipple shield.

To aid oral therapeutic administration to infants, a novel delivery technology, referred to as a Therapeutic Nipple Shield (TNS), was previously developed. It consists of a silicone nipple shield device and a dosage form containing a therapeutic (or Active Pharmaceutical Ingredient (API)) to enable delivery during breastfeeding. A range of dosage forms were investigated in past literature, but sufficient API release into human milk had not been achieved. The presented work illustrates the delivery of iron sulphate pentahydrate from liquid-core sodium alginate hydrogels, inserted into a commercially available ultra-thin silicone nipple shield into human milk during in-vitro breastfeeding simulation. Release of iron was quantified employing absorbance measurements of a salicylic assay. An absolute recovery of 44.35 ±â€¯5.43% of loaded iron(III)sulphate pentahydrate was obtained after 10.58 ±â€¯0.09 g of human milk had passed through the nipple shield. This finding is superior to previous investigations involving the delivery of zinc from rapidly disintegrating tablets and non-woven fibres within a TNS. Due to their superior delivery properties, ease of fabrication and cost-efficiency, liquid-core sodium alginate hydrogels consequently represent a promising dosage form for use as part of the TNS. Further improvements can be made to enhance handling stability and shelf-life characteristics.

Gene drives for schistosomiasis transmission control.

Schistosomiasis is one of the most important and widespread neglected tropical diseases (NTD), with over 200 million people infected in more than 70 countries; the disease has nearly 800 million people at risk in endemic areas. Although mass drug administration is a cost-effective approach to reduce occurrence, extent, and severity of the disease, it does not provide protection to subsequent reinfection. Interventions that target the parasites' intermediate snail hosts are a crucial part of the integrated strategy required to move toward disease elimination. The recent revolution in gene drive technology naturally leads to questions about whether gene drives could be used to efficiently spread schistosome resistance traits in a population of snails and whether gene drives have the potential to contribute to reduced disease transmission in the long run. Responsible implementation of gene drives will require solutions to complex challenges spanning multiple disciplines, from biology to policy. This Review Article presents collected perspectives from practitioners of global health, genome engineering, epidemiology, and snail/schistosome biology and outlines strategies for responsible gene drive technology development, impact measurements of gene drives for schistosomiasis control, and gene drive governance. Success in this arena is a function of many factors, including gene-editing specificity and efficiency, the level of resistance conferred by the gene drive, how fast gene drives may spread in a metapopulation over a complex landscape, ecological sustainability, social equity, and, ultimately, the reduction of infection prevalence in humans. With combined efforts from across the broad global health community, gene drives for schistosomiasis control could fortify our defenses against this devastating disease in the future.

Zinc delivery from non-woven fibres within a therapeutic nipple shield.

A Therapeutic Nipple Shield (TNS) was previously developed to respond to the global need for new infant therapeutic delivery technologies. However, the release efficiency for the same Active Pharmaceutical Ingredient (API) from different therapeutic matrices within the TNS formulation has not yet been investigated. To address this, in-vitro release of elemental zinc into human milk from two types of Texel non-woven fibre mats of varying thickness and different gram per square meter values, placed inside the TNS was explored and compared to the release from zinc-containing rapidly disintegrating tablets. In-vitro delivery was performed by means of a breastfeeding simulation apparatus, with human milk flow rates and suction pressure adjusted to physiologically relevant values, and release was quantified using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). It was found that a total recovery of 62-64 % elemental zinc was obtained after the human milk had passed through the fibre insert, amounting to a 20-48% increase compared to previous zinc delivery studies using rapidly disintegrating tablets within the TNS. This indicates that non-woven Texel fibre mats were identified as the superior dosage form for oral zinc delivery into human milk using a TNS.