Bioavailability of tetracyclines is substantially increased by administration of cyclosporine A, a non-specific efflux-pump blocker.

OBJECTIVES: To investigate how cyclosporine A, a nonspecific efflux-pump blocker, affects the plasma concentrations and oral bioavailability of tigecycline, oxytetracycline, chlortetracycline, doxycycline, minocycline, and tetracycline. METHODS: Broiler chickens were used as an animal model. The tetracyclines (10 mg/kg BW) were administered intravenously, orally, and orally with cyclosporine A (50 mg/kg BW; administration: oral or intravenous). After administration, plasma samples were taken, and their concentrations of tetracyclines were measured using high-performance liquid chromatography coupled with tandem mass spectrometry. For pharmacokinetic analyses of mean plasma concentrations versus time, compartmental and non-compartmental analyses were used. RESULTS: After oral administration of the tetracyclines, cyclosporine A administration (oral or intravenous) significantly (P < 0.05) increased the plasma concentrations, the bioavailability, the maximum plasma concentration, and the area under the curve of all the tetracyclines. Interestingly, the bioavailability of the tetracyclines was around two times higher after orally administering cyclosporine A than after intravenously administering it (P < 0.05). CONCLUSIONS: Cyclosporine A administration increases the plasma concentrations of orally administered tetracyclines. Although cyclosporine A also inhibits renal and hepatic clearance, these results strongly suggest that efflux pumps in the intestinal epithelium are involved in the regulation of tetracycline absorption from the gastrointestinal tract.

Transformation of Tetracycline by Manganese Peroxidase from Phanerochaete chrysosporium.

The negative impacts on the ecosystem of antibiotic residues in the environment have become a global concern. However, little is known about the transformation mechanism of antibiotics by manganese peroxidase (MnP) from microorganisms. This work investigated the transformation characteristics, the antibacterial activity of byproducts, and the degradation mechanism of tetracycline (TC) by purified MnP from Phanerochaete chrysosporium. The results show that nitrogen-limited and high level of Mn2+ medium could obtain favorable MnP activity and inhibit the expression of lignin peroxidase by Phanerochaete chrysosporium. The purified MnP could transform 80% tetracycline in 3 h, and the threshold of reaction activator (H2O2) was about 0.045 mmol L-1. After the 3rd cyclic run, the transformation rate was almost identical at the low initial concentration of TC (77.05-88.47%), while it decreased when the initial concentration was higher (49.36-60.00%). The antimicrobial potency of the TC transformation products by MnP decreased throughout reaction time. We identified seven possible degradation products and then proposed a potential TC transformation pathway, which included demethylation, oxidation of the dimethyl amino, decarbonylation, hydroxylation, and oxidative dehydrogenation. These findings provide a novel comprehension of the role of MnP on the fate of antibiotics in nature and may develop a potential technology for tetracycline removal.

Activated Carbon Fiber Cloth/Biomimetic Apatite: A Dual Drug Delivery System.

A biomaterial that is both bioactive and capable of controlled drug release is highly attractive for bone regeneration. In previous works, we demonstrated the possibility of combining activated carbon fiber cloth (ACC) and biomimetic apatite (such as calcium-deficient hydroxyapatite (CDA)) to develop an efficient material for bone regeneration. The aim to use the adsorption properties of an activated carbon/biomimetic apatite composite to synthetize a biomaterial to be used as a controlled drug release system after implantation. The adsorption and desorption of tetracycline and aspirin were first investigated in the ACC and CDA components and then on ACC/CDA composite. The results showed that drug adsorption and release are dependent on the adsorbent material and the drug polarity/hydrophilicity, leading to two distinct modes of drug adsorption and release. Consequently, a double adsorption approach was successfully performed, leading to a multifunctional and innovative ACC-aspirin/CDA-tetracycline implantable biomaterial. In a second step, in vitro tests emphasized a better affinity of the drug (tetracycline or aspirin)-loaded ACC/CDA materials towards human primary osteoblast viability and proliferation. Then, in vivo experiments on a large cortical bone defect in rats was carried out to test biocompatibility and bone regeneration ability. Data clearly highlighted a significant acceleration of bone reconstruction in the presence of the ACC/CDA patch. The ability of the aspirin-loaded ACC/CDA material to release the drug in situ for improving bone healing was also underlined, as a proof of concept. This work highlights the possibility of bone patches with controlled (multi)drug release features being used for bone tissue repair.

Controlled release of tetracycline hydrochloride from poly(ω-pentadecalactone-co-ε-caprolactone)/gelatin nanofibers.

Development of drug delivery systems is an extensively researched area in biomedical field. In recent years, there is an increasing interest on fabrication of biocompatible nanofibrous drug delivery systems. In the present study, poly(ω-pentadecalactone-co-ε-caprolactone)/gelatin nanofibrous membranes were fabricated for the controlled delivery and release of tetracycline hydrochloride (TCH) antibiotic. Poly(ω-pentadecalactone-co-ε-caprolactone) content provides an originality to the membrane, since it has been synthesized enzymatically previously. Varied amounts of tetracycline hydrochloride including poly(ω-pentadecalactone-co-ε-caprolactone)/gelatin (1:1, v:v) binary polymer blend was electrospun and characterizations (morphological and molecular structure, wettability characteristics, and thermal behavior) were applied to investigate the incorporation of drug molecule. Afterwards, in vitro drug release studies were carried out and mathematical modelling was applied to drug release data in order to clarify the transport mechanism of drug. TCH release profile comprised of an initial burst release in first hour and followed by a sustained release through 14 days which allowed sufficient antibacterial activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria. The presented drug delivery system may be applied as an antibacterial wound dressing device for skin infections.

A robust regenerated cellulose-based dual stimuli-responsive hydrogel as an intelligent switch for controlled drug delivery.

Constructing robust hydrogels with biodegradability and dual stimuli-responsive by utilizing natural polymer as raw materials remains a sustaining challenge. Herein, we proposed an interpenetrating strategy in which N-isopropyl acrylamide (NIPAM) and acrylamide (AM) block copolymers were introduced as the second network into the carboxymethyl cellulose single network gel (CMC gel) to construct a dual-network robust hydrogel (CMC/PNIPAM-co-PAM). The dual-network design strategy effectively improves the mechanical strength of CMC gel. The hydrogel suggests intelligent dual stimuli-responsive behavior to pH and temperature. Furthermore, the copolymerization of NIPAM and AM regulated the low critical solution temperature (LCST) of the hybrid hydrogel, making it close to the physiological temperature of the human body. With the aim of evaluating its application in drug delivery, we loaded tetracycline into the dual-network hydrogel and simulated its release process under the pH microenvironment of the small intestine and the physiological temperature to infer its potential application in intestinal inflammation treatments. Moreover, it is proved that the strong hydrogel possesses good cytocompatibility in vitro biocompatibility testing. In addition, the embedding of tetracycline makes the hydrogel excellent antioxidant performance. This dual-stimulus response integrated hydrogel is expected to play a critical role in drug delivery and targeted therapy.

Comparative pharmacokinetics of chlortetracycline, tetracycline, minocycline, and tigecycline in broiler chickens.

Tetracyclines continue to be important antimicrobials in veterinary medicine. However, the pharmacokinetics (PK) of tigecycline (TIG) and minocycline (MIN) in broiler chickens has not been investigated to date, and the PK of chlortetracycline (CTC) and tetracycline (TET) remains insufficiently researched, especially in terms of absorption. These antimicrobials have never been compared in a single setting in a single species; therefore, the aim of the present study was to compare the PK of TIG, MIN, CTC, and TET in broiler chickens. Each drug (10 mg/kg) was administered intravenously (IV) and orally (PO). The plasma concentrations of each drug were determined by liquid chromatography-tandem mass spectrometry, and the results were analyzed using compartmental and non-compartmental PK models. Despite the fact that all of the studied antimicrobials were administered at an identical IV dose, the area under the concentration-time curve between zero and the last sampling point (AUC0→t) for MIN (35,014 ± 3,274 µg × hour/mL) and CTC (41,851 ± 10,965 µg × hour/mL) differed significantly from that determined for TIG (18,866 ± 4,326 µg × hour/mL) and TET (17,817 ± 4,469 µg × hour/mL). After IV administration, the values of AUC0→t were also directly related to total body clearance values which were significantly higher for TIG (0.56 ± 0.14 L/hour × kg) and TET (0.60 ± 0.14 L/hour × kg) than for CTC (0.25 ± 0.05 L/hour × kg) and MIN (0.29 ± 0.03 L/hour × kg). In turn, after PO administration, TIG was absorbed in only 1.55% ± 0.82, and CTC in 30.54% ± 6.99, whereas the bioavailability of MIN and TET was relatively high at 52.33% ± 3.92 and 56.45% ± 9.71, respectively. The differences in PK parameters between these drugs, despite their structural similarities, suggest that active transport mechanisms may play a role in their absorption and distribution.

Rapid Raman Spectroscopic Analysis of Stress Induced Degradation of the Pharmaceutical Drug Tetracycline.

Stress factors caused by inadequate storage can induce the unwanted degradation of active compounds in pharmaceutical formulations. Resonance Raman spectroscopy is presented as an analytical tool for rapid monitoring of small concentration changes of tetracycline and the metabolite 4-epianhydrotetracycline. These degradation processes were experimentally induced by changes in temperature, humidity, and irradiation with visible light over a time period of up to 23 days. The excitation wavelength λexc = 413 nm was proven to provide short acquisition times for the simultaneous Raman spectroscopic detection of the degradation of tetracycline and production of its impurity in small sample volumes. Small concentration changes could be detected (down to 1.4% for tetracycline and 0.3% for 4-epianhydrotetracycline), which shows the potential of resonance Raman spectroscopy for analyzing the decomposition of pharmaceutical products.

Anti-HIV agent azidothymidine decreases Tet(X)-mediated bacterial resistance to tigecycline in Escherichia coli.

Recent emergence of high-level tigecycline resistance mediated by Tet(X3/X4) in Enterobacteriaceae undoubtably constitutes a serious threat for public health worldwide. Antibiotic adjuvant strategy makes antibiotic more effective against these resistant pathogens through interfering intrinsic resistance mechanisms or enhancing antibiotic actions. Herein, we screened a collection of drugs to identify compounds that are able to restore tigecycline activity against resistant pathogens. Encouragingly, we discovered that anti-HIV agent azidothymidine dramatically potentiates tigecycline activity against clinically resistant bacteria. Meanwhile, addition of azidothymidine prevents the evolution of tigecycline resistance in E. coli and the naturally occurring horizontal transfer of tet(X4). Evidence demonstrated that azidothymidine specifically inhibits DNA synthesis and suppresses resistance enzyme activity. Moreover, in in vivo infection models by Tet(X4)-expression E. coli, the combination of azidothymidine and tigecycline achieved remarkable treatment benefits including increased survival and decreased bacterial burden. These findings provide an effective regimen to treat infections caused by tigecycline-resistant Escherichia coli.

Synthetic hydroxyapatite: a recruiting platform for biologically active molecules.

Background and purpose - Targeted delivery of drugs is important to achieve efficient local concentrations and reduce systemic side effects. We hypothesized that locally implanted synthetic hydroxyapatite (HA) particles can act as a recruiting moiety for systemically administered drugs, leading to targeted drug accretion.Methods - Synthetic HA particles were implanted ectopically in a muscle pouch in rats, and the binding of systemically circulating drugs such as zoledronic acid (ZA), tetracycline and 18F-fluoride (18F) was studied. The local biological effect was verified in an implant integration model in rats, wherein a hollow implant was filled with synthetic HA particles and the animals were given systemic ZA, 2-weeks post-implantation. The effect of HA particle size on drug binding and the possibility of reloading HA particles were also evaluated in the muscle pouch.Results - The systemically administered biomolecules (ZA, tetracycline and 18F) all sought the HA moiety placed in the muscle pouch. Statistically significant higher peri-implant bone volume and peak force were observed in the implant containing HA particles compared with the empty implant. After a single injection of ZA at 2 weeks, micro HA particles showed a tendency to accumulate more 14C-zoledronic acid (14C-ZA) than nano-HA particles in the muscle pouch. HA particles could be reloaded when ZA was given again at 4 weeks, showing increased 14C-ZA accretion by 73% in microparticles and 77% in nanoparticles.Interpretation - We describe a novel method of systemic drug loading resulting in targeted accretion in locally implanted particulate HA, thereby biologically activating the material.

Fact versus Fiction: a Review of the Evidence behind Alcohol and Antibiotic Interactions.

Many antibiotics carry caution stickers that warn against alcohol consumption. Data regarding concurrent use are sparse. An awareness of data that address this common clinical scenario is important so health care professionals can make informed clinical decisions and address questions in an evidence-based manner. The purpose of this systematic review was to determine the evidence behind alcohol warnings issued for many common antimicrobials. The search was conducted from inception of each database to 2018 using PubMed, Medline via Ovid, and Embase. It included studies that involved interactions, effects on efficacy, and toxicity/adverse drug reactions (ADR) due to concomitant alcohol consumption and antimicrobials. All interactions were considered in terms of three components: (i) alteration in pharmacokinetics/pharmacodynamics (PK/PD) of antimicrobials and/or alcohol, (ii) change in antimicrobial efficacy, and (iii) development of toxicity/ADR. Available data support that oral penicillins, cefdinir, cefpodoxime, fluoroquinolones, azithromycin, tetracycline, nitrofurantoin, secnidazole, tinidazole, and fluconazole can be safely used with concomitant alcohol consumption. Data are equivocal for trimethoprim-sulfamethoxazole. Erythromycin may have reduced efficacy with alcohol consumption, and doxycycline may have reduced efficacy in chronic alcoholism. Alcohol low in tyramine may be consumed with oxazolidinones. The disulfiram-like reaction, though classically associated with metronidazole, occurs with uncertain frequency and with varied severity. Cephalosporins with a methylthiotetrazole (MTT) side chain or a methylthiodioxotriazine (MTDT) ring, ketoconazole, and griseofulvin have an increased risk of a disulfiram-like reaction. Alcohol and antimicrobial interactions are often lacking evidence. This review questions common beliefs due to poor, often conflicting data and identifies important knowledge gaps.

Bismuth Concentrations in Patients Treated in Real-Life Practice with a Bismuth Subcitrate-Metronidazole-Tetracycline Preparation: The SAPHARY Study.

INTRODUCTION: A fixed-dose association of bismuth subcitrate, metronidazole and tetracycline (BMT) (Pylera®, Allergan, NJ, USA) was made available in France in 2013 for the eradication of Helicobacter pylori. Due to a historical issue of bismuth encephalopathy, the French Health Authorities requested a study of blood and plasma bismuth concentrations with BMT in daily practice. AIMS: The aim of the study was to measure eventual bismuth accumulation and neurological toxicity in patients prescribed BMT. METHODS: Patients initiating BMT for H. pylori between March 2014 and December 2015 were included. A blood sample was taken before first BMT intake and 24 h after the last intake, for assay of bismuth. A concentration > 50 µg/L was considered abnormal. Neurological complaints were assessed at inclusion, at the end of the 10-day treatment course, and 28 days later. RESULTS: 202 patients were included, of whom 190 took at least one dose of BMT, and 167 provided both required blood samples. Mean blood bismuth concentrations after the BMT course were 16.9 µg/L (95% confidence interval 15.6-18.3). Concentrations were > 50 µg/L (56.0 µg/L and 50.9 µg/L) in two elderly patients, one of whom presented mild, transient memory impairment during treatment. Non-serious neurological symptoms occurred in 20% of all patients and treatment failure was documented in 5% of patients. CONCLUSIONS: In this study measuring blood bismuth concentrations in real-life practice, in < 1% of patients the BMT course resulted in blood bismuth concentrations > 50 µg/L. No serious neurological adverse events were observed. STUDY REGISTRATION: EU-PAS register EUPAS3142 at www.encepp.eu ; ENCePP study seal.

Bone-targeted delivery of simvastatin-loaded PEG-PLGA micelles conjugated with tetracycline for osteoporosis treatment.

This study aimed to investigate the improved therapeutic efficacy and pharmacokinetic profiles of simvastatin (SIM) with imparted bone targeting potential using tetracycline-mediated PEG-PLGA (TC-PEG-PLGA) micelles in osteoporotic rats. The SIM-loaded TC-PEG-PLGA (TC-PEG-PLGA/SIM) micelles were evaluated for particle size, morphology, stability, loading efficiency, cell viability, bone mineral binding ability in vitro, mineralization, pharmacokinetics, and pharmacodynamics. TC-PEG-PLGA conjugates were successfully and could self-assembly form micelles in aqueous medium with a 19.4 µg/mL critical micelle concentration. Then, TC-PEG-PLGA/SIM micelles were prepared with solvent diffusion method, and the obtained micelles (56.21 ± 7.39 nm average size; 81.8 ± 3.1% encapsulation efficiency; and 7.56 ± 0.27% drug loading) led to the prolonged release of SIM from micelles. Cellular uptake test indicated that TC had no effects on micellar internalization and micellar internalization was mainly involved with clathrin-mediated endocytic pathway. In vivo pharmacokinetic results indicated that TC-PEG-PLGA/SIM micelles exhibited a significantly prolonged time in systemic circulation and were preferentially accumulated in bone tissue. TC-PEG-PLGA/SIM micelles showed better therapeutic effects, as reflected by the improved bone mineral density, bone mineral content, and bone mechanical strength. Overall, these results suggested that TC-PEG-PLGA/SIM micelles provide several advantages, including prolonged systemic circulation, enhanced bone tissue distribution, and improved therapeutic outcomes in osteoporotic rats.

Construction of a simple evaluation system for the intestinal absorption of an orally administered medicine using Bombyx mori larvae.

Human intestinal absorption is estimated using a human colon carcinoma cell line (Caco-2) cells from human colorectal adenocarcinoma, intestinal perfusion, or a mammalian model. These current evaluation systems are limited in their ability to estimate human intestinal absorption. In addition, in vivo evaluation systems using laboratory animals such as mice and rats entail animal ethics problems, and it is difficult to screen compounds on a large scale at the drug discovery stage. Thus, we propose the use of Bombyx mori larvae for evaluation of intestinal absorption of compounds as an alternative system in this study. First, to compare the characteristics among Caco-2 cells, human intestine, and B. mori larval midgut, we analyzed their RNA-seq data, and we found 26 drug transporters common to humans and B. mori. Next, we quantitatively developed an oral administration technique in B. mori and established a method using silkworm B. mori larvae that can easily estimate the intestinal permeability of compounds. Consequently, we could determine the dose and technique for oral administration in B. mori larvae. We also developed a B. mori model to evaluate the intestinal permeability of orally administered. Our constructed evaluation system will be useful for evaluating intestinal permeability in medical drug development.

Bioavailability of Soil-Sorbed Tetracycline to Escherichia coli under Unsaturated Conditions.

Increasing concentrations of anthropogenic antibiotics in soils are partly responsible for the proliferation of bacterial antibiotic resistance. However, little is known about how soil-sorbed antibiotics exert selective pressure on bacteria in unsaturated soils. This study investigated the bioavailability of tetracycline sorbed on three soils (Webster clay loam, Capac sandy clay loam, and Oshtemo loamy sand) to a fluorescent Escherichia coli bioreporter under unsaturated conditions using agar diffusion assay, microscopic visualization, and model simulation. Tetracycline sorbed on the soils could be desorbed and become bioavailable to the E. coli cells at matric water potentials of -2.95 to -13.75 kPa. Bright fluorescent rings were formed around the tetracycline-loaded soils on the unsaturated agar surfaces, likely due to radial diffusion of tetracycline desorbed from the soils, tetracycline uptake by the E. coli cells, and its inhibition on E. coli growth, which was supported by the model simulation. The bioavailability of soil-sorbed tetracycline was much higher for the Oshtemo soil, probably due to faster diffusion of tetracycline in coarse-textured soils. Decreased bioavailability of soil-sorbed tetracycline at lower soil water potential likely resulted from reduced tetracycline diffusion in soil pore water at smaller matric potential and/or suppressed tetracycline uptake by E. coli at lower osmotic potential. Therefore, soil-sorbed tetracycline could still exert selective pressure on the exposed bacteria, which was influenced by soil physical processes controlled by soil texture and soil water potential.

Tetracycline-incorporated polymer nanofibers as a potential dental implant surface modifier.

This study investigated the antimicrobial and osteogenic properties of titanium (Ti) disks superficially modified with tetracycline (TCH)-incorporated polymer nanofibers. The experiments were carried out in two phases. The first phase dealt with the synthesis and characterization (i.e., morphology, mechanical strength, drug release, antimicrobial activity, and cytocompatibility) of TCH-incorporated fibers. The second phase was dedicated to evaluating both the antimicrobial and murine-derived osteoprecursor cell (MC3T3-E1) response of Ti-modified with TCH-incorporated fibers. TCH was successfully incorporated into the submicron-sized and cytocompatible fibers. All TCH-incorporated mats presented significant antimicrobial activity against periodontal pathogens. The antimicrobial potential of the TCH-incorporated fibers-modified Ti was influenced by both the TCH concentration and bacteria tested. At days 5 and 7, a significant increase in MC3T3-E1 cell number was observed for TCH-incorporated nanofibers-modified Ti disks when compared to that of TCH-free nanofibers-modified Ti-disks and bare Ti. A significant increase in alkaline phosphatase (ALP) levels on the Ti disks modified with TCH-incorporated nanofiber on days 7 and 14 was seen, suggesting that the proposed surface promotes early osteogenic differentiation. Collectively, the data suggest that TCH-incorporated nanofibers could function as an antimicrobial surface modifier and osteogenic inducer for Ti dental implants. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2085-2092, 2017.

Tetracycline uptake and metabolism by vetiver grass (Chrysopogon zizanioides L. Nash).

Environmental contamination by antibiotics not only perturbs the ecological balance but also poses a risk to human health by promoting the development of multiantibiotic-resistant bacteria. This study focuses on identifying the biochemical pathways associated with tetracycline (TC) transformation/degradation in vetiver grass that has the potential to be used as a biological remediation system in TC-contaminated water sources. A hydroponic experimental setup was used with four initial TC concentrations (0, 5, 35, 75 ppm), and TC uptake was monitored over a 30-day period. Results show that TC transformation in the media occurred during the first 5 days, where a decrease in the parent compound and an increase in the concentration of the isomers such as epitetracycline (ETC) and anhyrotetracycline (ATC) occurred, and TC disappeared in 20 days in tanks with vetiver grass. However, the isomers ETC and ATC remained in the control tanks for the duration of the trial. Transformation products of TC in plant tissue were analyzed by using ultra HPLC high-resolution Orbitrap mass spectrometery (HRMS/MS), which indicates amide hydrolysis of TC in vetiver roots. Metabolic profiling revealed that glyoxylate metabolism, TCA cycle, biosynthesis of secondary metabolites, tryptophan metabolism, and inositol phosphate metabolism were impacted in vetiver root by TC treatment.

Curdlan in fibers as carriers of tetracycline hydrochloride: Controlled release and antibacterial activity.

Curdlan (CURD) and polyethylene oxide were used to synthesize nanofibers as carriers of hydro soluble tetracycline hydrochloride (TCH). The viscosity, surface tension and conductivity of the precursor multicomponent aqueous solutions were determined and adjusted to produce defect-free fiber webs. Except for a slight increase in diameter, the addition of TCH did not affect the original morphology of the CURD/PEO nanofibers, as determined by FE-SEM imaging. However, the thermal stability of the system was enhanced (TGA and DSC). Moreover, water resistance, as measured with 24-h immersion tests, was observed upon crosslinking with glutaraldehyde. In-vitro activity measurements indicated a sustained and controlled TCH time-release pattern and excellent antibacterial activity against E. coli, as assessed by UV-vis spectroscopy and viable cell counting, respectively. Overall, we propose nanofibers based on CURD as promising platforms for scaffolds for wound dressing and drug delivery.

Time-kill curve analysis and pharmacodynamic modelling for in vitro evaluation of antimicrobials against Neisseria gonorrhoeae.

BACKGROUND: Gonorrhoea is a sexually transmitted infection caused by the Gram-negative bacterium Neisseria gonorrhoeae. Resistance to first-line empirical monotherapy has emerged, so robust methods are needed to evaluate the activity of existing and novel antimicrobials against the bacterium. Pharmacodynamic models describing the relationship between the concentration of antimicrobials and the minimum growth rate of the bacteria provide more detailed information than the MIC only. RESULTS: In this study, a novel standardised in vitro time-kill curve assay was developed. The assay was validated using five World Health Organization N. gonorrhoeae reference strains and a range of ciprofloxacin concentrations below and above the MIC. Then the activity of nine antimicrobials with different target mechanisms was examined against a highly antimicrobial susceptible clinical strain isolated in 1964. The experimental time-kill curves were analysed and quantified with a previously established pharmacodynamic model. First, the bacterial growth rates at each antimicrobial concentration were estimated with linear regression. Second, we fitted the model to the growth rates, resulting in four parameters that describe the pharmacodynamic properties of each antimicrobial. A gradual decrease of bactericidal effects from ciprofloxacin to spectinomycin and gentamicin was found. The beta-lactams ceftriaxone, cefixime and benzylpenicillin showed bactericidal and time-dependent properties. Chloramphenicol and tetracycline were purely bacteriostatic as they fully inhibited the growth but did not kill the bacteria. We also tested ciprofloxacin resistant strains and found higher pharmacodynamic MICs (zMIC) in the resistant strains and attenuated bactericidal effects at concentrations above the zMIC. CONCLUSIONS: N. gonorrhoeae time-kill curve experiments analysed with a pharmacodynamic model have potential for in vitro evaluation of new and existing antimicrobials. The pharmacodynamic parameters based on a wide range of concentrations below and above the MIC provide information that could support improving future dosing strategies to treat gonorrhoea.

Preparation and characterization of aligned porous PCL/zein scaffolds as drug delivery systems via improved unidirectional freeze-drying method.

A novel type of drug-delivery scaffold based on poly(ε-caprolactone) (PCL) and zein blends was prepared by improved unidirectional freeze-drying. Scaffolds with tube-like pore structure and high porosity, up to 89%, were obtained by adjusting the concentration of the PCL and zein solutions. Characters of the prepared scaffolds, such as microstructural, porosity, and compressive strength, were evaluated. The hydrophilicity and the degradability of the composite films were investigated in contact with phosphate buffer saline (PBS). It was found that the presence of zein accelerates the degradation rate of the scaffolds in the period time of investigation (28days). The results showed an acceptable way for controlling the in vitro degradation behavior of PCL composite scaffolds by adapting the concentration of zein. In vitro protein release and degradation results revealed that the absolute weight loss of the PCL/zein scaffolds exhibited an increasing trend by increasing the amount of zein concentration in the scaffolds. The drug delivery capability of the scaffolds was tested using tetracycline hydrochloride (TCH). Sustained release of the drug was obtained, and it was found that the proportion of zein in the scaffold had a great impact on the drug release kinetics. The results demonstrated the potential of the PCL/zein biocomposite scaffolds as a suitable candidate in tissue engineering strategies for bone defect treatment.