Streptococcus pneumoniae antimicrobial resistance decreased in the Helsinki Metropolitan Area after routine 10-valent pneumococcal conjugate vaccination of infants in Finland

Since the introduction of 10-valent pneumococcal conjugate vaccine (PCV10) into the Finnish national vaccination program in September 2010, the incidence of invasive pneumococcal disease in children has decreased steeply in Finland. We studied the antimicrobial susceptibility of invasive and non-invasive Streptococcus pneumoniae (pneumococcus) isolated in the Helsinki Metropolitan Area during 2009-2014. We divided the data into two age groups: isolates from patients <5 years old and ae5 years old. We also studied the serotype distribution of invasive isolates and of a subset of non-invasive multidrug-resistant isolates. The invasive isolate numbers recovered from patients aged <5 years old declined from 33/228 (15%) in 2009 to 8/208 (4%) in 2014 (p <0.001) and non-invasive isolate numbers declined during the same time period from 221/595 (37%) to 119/432 (28%) (p <0.001). At the same time, the proportion of penicillin non-susceptible non-invasive isolates in this age group decreased from 25% (56/220) to 13% (15/119) (p = 0.001) and multidrug-resistant isolates from 22% (49/220) to 6% (7/119) (p <0.001), respectively. The number of PCV10 serotype isolates also decreased among the serotyped multidrug-resistant non-invasive isolates. Among patients aged ae5 years old, the isolate numbers did not show a similar decreasing trend compared to the younger group and, further, the number of non-PCV10 serotype isolates increased in invasive cases. To conclude, the antimicrobial non-susceptibility of pneumococcus has decreased markedly, especially among young patients (<5 years old), following PCV10 implementation in Finland.Peer reviewe

Prevention of Gestational Diabetes: Design of a Cluster-Randomized Controlled Trial and One-Year Follow-Up

<p>Abstract</p> <p>Background</p> <p>Annual prevalence of gestational diabetes mellitus (GDM) is 12.5% among Finnish pregnant women. The prevalence is expected to rise with the increasing overweight among women before pregnancy. Physical activity and diet are both known to have favourable effects on insulin resistance and possibly on the risk of GDM. We aimed to investigate, whether GDM can be prevented by counseling on diet, physical activity and gestational weight gain during pregnancy.</p> <p>Methods/Design</p> <p>A cluster-randomized controlled trial was conducted in 14 municipalities in the southern part of Finland. Pairwise randomization was performed in order to take into account socioeconomic differences. Recruited women were at 8-12 weeks' gestation and fulfilled at least one of the following criteria: body mass index ≥ 25 kg/m², history of earlier gestational glucose intolerance or macrosomic newborn (> 4500 g), age ≥ 40 years, first or second degree relative with history of type 1 or 2 diabetes. Main exclusion criterion was pathological oral glucose tolerance test (OGTT) at 8-12 weeks' gestation. The trial included one counseling session on physical activity at 8-12 weeks' gestation and one for diet at 16-18 weeks' gestation, and three to four booster sessions during other routine visits. In the control clinics women received usual care. Information on height, weight gain and other gestational factors was obtained from maternity cards. Physical activity, dietary intake and quality of life were followed by questionnaires during pregnancy and at 1-year postpartum. Blood samples for lipid status, hormones, insulin and OGTT were taken at 8-12 and 26-28 weeks' gestation and 1 year postpartum. Workability and return to work were elicited by a questionnaire at 1- year postpartum. Linkage to the national birth register of years 2007-2009 will provide information on perinatal complications and GDM incidence among the non-participants of the study. Cost-effectiveness evaluation will be based on quality-adjusted life years. This study has received ethical approval from the Ethical board of Pirkanmaa Hospital District.</p> <p>Discussion</p> <p>The study will provide information on the effectiveness and cost-effectiveness of gestational physical activity and dietary counseling on prevention of GDM in a risk group of women. Also information on the prevalence of GDM and postpartum metabolic syndrome will be gained. Results on maintaining the possible health behaviour changes are important in order to prevent chronic diseases such as cardiovascular disease and diabetes.</p> <p>Trial registration</p> <p>The trial is registered ISRCTN 33885819</p

Corneal and conjunctival drug permeability: Systematic comparison and pharmacokinetic impact in the eye

On the surface of the eye, both the cornea and conjunctiva are restricting ocular absorption of topically applied drugs, but barrier contributions of these two membranes have not been systemically compared. Herein, we studied permeability of 32 small molecular drug compounds across an isolated porcine cornea and built a quantitative structure-property relationship (QSPR) model for the permeability. Corneal drug permeability (data obtained for 25 drug molecules) showed a 52-fold range in permeability (0.09-4.70x10(-6) cm/s) and the most important molecular descriptors in predicting the permeability were hydrogen bond donor, polar surface area and halogen ratio. Corneal permeability values were compared to their conjunctival drug permeability values. Ocular drug bioavailability and systemic absorption via conjunctiva were predicted for this drug set with pharmacokinetic calculations. Drug bioavailability in the aqueous humour was simulated to be <5% and trans-conjunctival systemic absorption was 34-79% of the dose. Loss of drug across the conjunctiva to the blood circulation restricts significantly ocular drug bioavailability and, therefore, ocular absorption does not increase proportionally with the increasing corneal drug permeability.Peer reviewe

Intravitreal Polymeric Nanocarriers with Long Ocular Retention and Targeted Delivery to the Retina and Optic Nerve Head Region

Posterior eye tissues, such as retina, are affected in many serious eye diseases, but drug delivery to these targets is challenging due to various anatomical eye barriers. Intravitreal injections are widely used, but the intervals between invasive injections should be prolonged. We synthesized and characterized (1H NMR, gel permeation chromatography) block copolymers of poly(ethylene glycol), poly(caprolactone), and trimethylene carbonate. These polymers self-assembled to polymersomes and polymeric micelles. The mean diameters of polymersomes and polymeric micelles, about 100 nm and 30–50 nm, respectively, were obtained with dynamic light scattering. Based on single particle tracking and asymmetric flow field-flow fractionation, the polymeric micelles and polymersomes were stable and diffusible in the vitreous. The materials did not show cellular toxicity in cultured human umbilical vein endothelial cells in the Alamar Blue Assay. Pharmacokinetics of the intravitreal nanocarriers in the rabbits were evaluated using in vivo fluorophotometry. The half-lives of the polymersomes (100 nm) and the micelles (30 nm) were 11.4–32.7 days and 4.3–9.5 days. The intravitreal clearance values were 1.7–8.7 µL/h and 3.6–5.4 µL/h for polymersomes and polymeric micelles, respectively. Apparent volumes of distribution of the particles in the rabbit vitreous were 0.6–1.3 mL for polymeric micelles and 1.9–3.4 mL for polymersomes. Polymersomes were found in the vitreous for at least 92 days post-dosing. Furthermore, fundus imaging revealed that the polymersomes accumulated near the optic nerve and retained there even at 111 days post-injection. Polymersomes represent a promising technology for controlled and site-specific drug delivery in the posterior eye segment

Understanding dexamethasone kinetics in the rabbit tear fluid : Drug release and clearance from solution, suspension and hydrogel formulations

Rapid precorneal loss of topically applied eye drops limits ocular drug absorption. Controlling release and precorneal residence properties of topical formulations may improve ocular drug bioavailability and duration of action. In this study, we evaluated in vivo ocular pharmacokinetics of dexamethasone in rabbits after application of a drug solution (0.01%), suspension (Maxidex (R) 0.1%), and hydrogels of 2-hydroxyethyl methacrylate (HEMA) and acrylic acid (AAc) copolymers. The rabbits received a single eyedrop (solution or suspension) or dexamethasone-loaded hydrogel topically. Dexamethasone in tear fluid was sampled with glass capillaries and quantitated by LC-MS/MS. Higher dexamethasone exposure (AUC) in the tear fluid was observed with the suspension (approximate to 3.6-fold) and hydrogel (12.8-fold) as compared to the solution. During initial 15 min postapplication, the highest AUC of dissolved dexamethasone was seen after hydrogel application (368 min*mu g/ mL) followed by suspension (109.9 min*mu g/mL) and solution (28.7 min*mu g/mL. Based on kinetic simulations, dexamethasone release from hydrogels in vivo and in vitro is comparable. Our data indicate that prolonged exposure of absorbable dexamethasone in tear fluid is reached with hydrogels and suspensions. Pharmacokinetic understanding of formulation behavior in the lacrimal fluid helps in the design of dexamethasone delivery systems with improved ocular absorption and prolonged duration of action.Peer reviewe

Role of retinal pigment epithelium permeability in drug transfer between posterior eye segment and systemic blood circulation

Retinal pigment epithelium (RPE) is a major part of blood-retinal barrier that affects drug elimination from the vitreous to the blood and drug distribution from blood circulation into the eye. Even though drug clearance from the vitreous has been well studied, the role of RPE in the process has not been quantified. The aim of this work was to study the role of RPE clearance (CLRpE) as part of drug elimination from the vitreous and ocular drug distribution from the systemic blood circulation. We determined the bidirectional permeability of eight small molecular weight drugs and bevacizumab antibody across isolated bovine RPE-choroid. Permeability of small molecules was 10(-6) -10(-5)cm/s showing 13-15 fold range of outward and inward permeation, while permeability of bevacizumab was lower by 2-3 orders of magnitude. Most small molecular weight drugs showed comparable outward (vitreous-to-choroid) and inward (choroid-to-vitreous) permeability across the RPEchoroid, except ciprofloxacin and ketorolac that had an over 6 and 14-fold higher outward than inward permeability, respectively, possibly indicating active transport, Six of seven tested small molecular weight drugs had outward CLRPE values that were comparable with their intravitreal clearance (CLIvr) values (0.84-2.6 fold difference). On the contrary, bevacizumab had an outward CLRPE that was only 3.5% of the CLIvt, proving that its main route of elimination (after intravitreal injection) is not RPE permeation. Experimental values were used in pharmacokinetic simulations to assess the role of the RPE in drug transfer from the systemic blood circulation to the vitreous (CLBv). We conclude that for small molecular weight drugs the RPE is an important route in drug transfer between the vitreal cavity and blood, whereas it effectively hinders the movement of bevacizumab from the vitreous to the systemic circulation.Peer reviewe

Partitioning and Spatial Distribution of Drugs in Ocular Surface Tissues

Ocular drug absorption after eye drop instillation has been widely studied, but partitioning phenomena and spatial drug distribution are poorly understood. We investigated partitioning of seven beta-blocking drugs in corneal epithelium, corneal stroma, including endothelium and conjunctiva, using isolated porcine tissues and cultured human corneal epithelial cells. The chosen beta-blocking drugs had a wide range (-1.76-0.79) of n-octanol/buffer solution distribution coefficients at pH 7.4 (Log D-7.4). In addition, the ocular surface distribution of three beta-blocking drugs was determined by matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) after their simultaneous application in an eye drop to the rabbits in vivo. Studies with isolated porcine corneas revealed that the distribution coefficient (K-p) between the corneal epithelium and donor solution showed a positive relationship and good correlation with Log D-7.4 and about a 50-fold range of K-p values (0.1-5). On the contrary, K-p between corneal stroma and epithelium showed an inverse (negative) relationship and correlation with Log D-7.4 based on a seven-fold range of K-p values. In vitro corneal cell uptake showed a high correlation with the ex vivo corneal epithelium/donor K-p values. Partitioning of the drugs into the porcine conjunctiva also showed a positive relationship with lipophilicity, but the range of K-p values was less than with the corneal epithelium. MALDI-IMS allowed simultaneous detection of three compounds in the cornea, showed data in line with other experiments, and revealed uneven spatial drug distribution in the cornea. Our data indicate the importance of lipophilicity in defining the corneal pharmacokinetics and the K-p values are a useful building block in the kinetic simulation models for topical ocular drug administration.Peer reviewe

Ocular intracameral pharmacokinetics for a cocktail of timolol, betaxolol and atenolol in rabbits

The mechanisms of drug clearance from the aqueous humor are poorly defined. In this study, a cocktail approach was used to simultaneously determine the pharmacokinetics of three β-blocker agents after intracameral (ic) injection into the rabbit eyes. Aqueous humor samples were collected and analyzed using LC–MS/MS to determine drug concentrations. Pharmacokinetic parameters were obtained using a compartmental fitting approach, and the estimated clearance, volume of distribution, and half-life values were the following: atenolol (6.44 μL/min, 687 μL, and 73.87 min), timolol (19.30 μL/min, 937 μL, and 33.64 min), and betaxolol (32.20 μL/min, 1421 μL, and 30.58 min). Increased compound lipophilicity (atenolol < timolol < betaxolol) resulted in higher clearance and volume of distributions in the aqueous humor. Clearance of timolol and betaxolol is about 10 times higher than the aqueous humor outflow, demonstrating the importance of other elimination routes (e.g., uptake to iris and ciliary body and subsequent elimination via blood flow)

Distribution of Small Molecular Weight Drugs into the Porcine Lens : Studies on Imaging Mass Spectrometry, Partition Coefficients, and Implications in Ocular Pharmacokinetics

Lens is the avascular tissue in the eye between the aqueous humor and vitreous. Drug binding to the lens might affect ocular pharmacokinetics, and the binding may also have a pharmacological role in drug-induced cataract and cataract treatment. Drug distribution in the lens has been studied in vitro with many compounds; however, the experimental methods vary, no detailed information on distribution between the lens sublayers exist, and the partition coefficients are reported rarely. Therefore, our objectives were to clarify drug localization in the lens layers and establish partition coefficients for a wide range of molecules. Furthermore, we aimed to illustrate the effect of lenticular drug binding on overall ocular drug pharmacokinetics. We studied the distribution of 16 drugs and three fluorescent dyes in whole porcine lenses in vitro with imaging mass spectrometry and fluorescence microscopy techniques. Furthermore, we determined lens/buffer partition coefficients with the same experimental setup for 28 drugs with mass spectrometry. Finally, the effect of lenticular binding of drugs on aqueous humor drug exposure was explored with pharmacokinetic simulations. After 4 h, the drugs and the dyes distributed only to the outermost lens layers (capsule and cortex). The lens/buffer partition coefficients for the drugs were low, ranging from 0.05 to 0.8. On the basis of the pharmacokinetic simulations, a high lens-aqueous humor partition coefficient increases drug exposure in the lens but does not significantly alter the pharmacokinetics in the aqueous humor. To conclude, the lens seems to act mainly as a physical barrier for drug distribution in the eye, and drug binding to the lens affects mainly the drug pharmacokinetics in the lens.Peer reviewe

Topical ocular pharmacokinetics and bioavailability for a cocktail of atenolol, timolol and betaxolol in rabbits

Ocular bioavailability after eye drops administration is an important, but rarely determined, pharmacokinetic parameter. In this study, we measured the pharmacokinetics of a cocktail of three beta blockers after their topical administration into the albino rabbit eye. Samples from aqueous humour were analysed with LC-MS/MS. The pharmacokinetic parameters were estimated using compartmental and non-compartmental analyses. The ocular bioavailability was covering broad range of values: atenolol (0.07 %), timolol (1.22%, 1.51%) and betaxolol (3.82%, 4.31%). Absolute ocular bioavailability presented a positive trend with lipophilicity and the values showed approximately 60-fold range. The generated data enhances our understanding for ocular pharmacokinetics of drugs and may be utilized in pharmacokinetic model building in ophthalmic drug development.Peer reviewe