Enhancing linezolid activity in the treatment of oral biofilms using novel chitosan microneedles with iontophoretic control.

This study aimed to prepare and assess active microneedle (MN) patches based on a novel biomaterial and their effective coupled (physical and electrical) transdermal delivery of a model drug (Linezoid). Modified MN patches (e.g. fabricated from Linezoid, boronated chitosan, polyvinyl alcohol and D-sorbitol) were engineered using a vacuum micromoulding method. Physicochemical, FTIR (Fourier transform infrared), in-silico, structural and thermal analysis of prepared formulations were conducted to ascertain MN quality, composition and integrity. In-vitro mechanical tests, membrane toxicity, drug release, antibiofilm, ex-vivo mucoadhesion, insertion and in-vivo antibiofilm studies were performed to further validate viability of the coupled system. Optimized MN patch formulation (CSHP3 - comprising of 3 % w/v boronated chitosan, 3.5 % w/v PVA and 10 % w/w D-sorbitol) exhibited sharp-tipped, equi-distant and uniform-surfaced micron-scaled projections with conforming physicochemical features. FTIR analysis confirmed modification (i.e., boronation) of chitosan and compatibility as well as interaction between CSHP3 constituents. In-silico analysis indicated non-covalent interactions between all formulation constituents. Moreover, boronated chitosan-mucin glycoprotein complex showed a stronger bonding (∼1.86 times higher CScore) as compared to linezolid-mucin counterpart. Thermal analysis indicated amorphous nature of CSHP3. A âˆ¼ 1.42 times higher tensile strength was displayed by CSHP3 as compared to control (i.e., pure chitosan, polyvinyl alcohol and D-sorbitol-based MN patch). Membrane toxicity study indicated non-toxic and physiological compatible nature of CSHP3. Within 90 min, 91.99 ± 2.3 % linezolid was released from CSHP3. During release study on agarose gel, CSHP3-iontophoresis treatment resulted in a âˆ¼ 1.78 and âˆ¼ 1.20 times higher methylene blue-covered area and optical density, respectively, within 60 min as compared to CSHP3 treatment alone. Staphylococcus aureus biofilms treated with CSHP3 exhibited 65 ± 4.2 % reduction in their mass. CSHP3 MN patches remained adhered to the rabbit oral mucosa for 6 ± 0.15 h. Mucosa treated with CSHP3 and CSHP3-iontophoresis combination showed a generation of pathways in the epithelium layers without any damage to the underlying lamina propria. Eradication of Staphylococcus aureus from oral mucosal wounds and complete tissue regeneration was recorded following 7-day treatment using CSHP3-iontophoresis coupled approach.

Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities.

Linezolid is a drug with proven human antitubercular activity whose use is limited to highly drug-resistant patients because of its toxicity. This toxicity is related to its mechanism of action─linezolid inhibits protein synthesis in both bacteria and eukaryotic mitochondria. A highly selective and potent series of oxazolidinones, bearing a 5-aminomethyl moiety (in place of the typical 5-acetamidomethyl moiety of linezolid), was identified. Linezolid-resistant mutants were cross-resistant to these molecules but not vice versa. Resistance to the 5-aminomethyl molecules mapped to an N-acetyl transferase (Rv0133) and these mutants remained fully linezolid susceptible. Purified Rv0133 was shown to catalyze the transformation of the 5-aminomethyl oxazolidinones to their corresponding N-acetylated metabolites, and this transformation was also observed in live cells of Mycobacterium tuberculosis. Mammalian mitochondria, which lack an appropriate N-acetyltransferase to activate these prodrugs, were not susceptible to inhibition with the 5-aminomethyl analogues. Several compounds that were more potent than linezolid were taken into C3HeB/FeJ mice and were shown to be highly efficacious, and one of these (9) was additionally taken into marmosets and found to be highly active. Penetration of these 5-aminomethyl oxazolidinone prodrugs into caseum was excellent. Unfortunately, these compounds were rapidly converted into the corresponding 5-alcohols by mammalian metabolism which retained antimycobacterial activity but resulted in substantial mitotoxicity.

Formulation and Optimization of Solid Lipid Nanoparticle-based Gel for Dermal Delivery of Linezolid using Taguchi Design.

BACKGROUND: Linezolid (LNZ) is a synthetic oxazolidinone antibiotic approved for the treatment of uncomplicated and complicated skin and soft tissue infections caused by gram-positive bacteria. Typically, LNZ is administered orally or intravenously in most cases. However, prolonged therapy is associated with various side effects and lifethreatening complications. Cutaneous application of LNZ will assist in reducing the dose, hence minimizing the unwanted side/adverse effects associated with oral administration. Dermal delivery provides an alternative route of administration, facilitating a local and sustained concentration of the antimicrobial at the site of infection. OBJECTIVE: The current research work aimed to formulate solid lipid nanoparticles (SLNs) based gel for dermal delivery of LNZ in the management of uncomplicated skin and soft tissue infections to maximise its benefits and minimise the side effects. METHODS: SLNs were prepared by high-shear homogenisation and ultrasound method using Dynasan 114 as solid lipid and Pluronic F-68 as surfactant. The effect of surfactant concentration, drug-to-lipid ratio, and sonication time was investigated on particle size, zeta potential, and entrapment efficiency using the Taguchi design. The main effect plot of means and signal-to-noise ratio were generated to determine the optimized formulation. The optimized batch was formulated into a gel, and ex vivo permeation study, in vitro and in vivo antibacterial activity were conducted. RESULTS: The optimised process parameters to achieve results were 2% surfactant concentration, a drug-to-lipid ratio of 1:2, and 360 s of sonication time. The optimized batch was 206.3± 0.17nm in size with a surface charge of -24.4± 4.67mV and entrapment efficiency of 80.90 ± 0.45%. SLN-based gel demonstrated anomalous transport with an 85.43% in vitro drug release. The gel showed a 5.03 ± 0.15 cm zone of inhibition while evaluated for in vitro antibacterial activity against Staphylococcus aureus. Ex vivo skin permeation studies demonstrated 20.308% drug permeation and 54.96% cutaneous deposition. In-vivo results showed a significant reduction in colony-forming units in the group treated with LNZ SLN-based gel. CONCLUSION: Ex vivo studies ascertain the presence of the drug at the desired site and improve therapy. In vivo results demonstrated the ability of SLN-based gel to significantly reduce the number of bacteria in the stripped infection model. The utilization of SLN as an LNZ carrier holds significant promise in dermal delivery.

Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics.

The antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has demonstrated that linezolid does not inhibit peptide bond formation at all sequences but rather acts in a context-specific manner, namely when alanine occupies the penultimate position of the nascent chain. However, the molecular basis for context-specificity has not been elucidated. Here we show that the second-generation oxazolidinone radezolid also induces stalling with a penultimate alanine, and we determine high-resolution cryo-EM structures of linezolid- and radezolid-stalled ribosome complexes to explain their mechanism of action. These structures reveal that the alanine side chain fits within a small hydrophobic crevice created by oxazolidinone, resulting in improved ribosome binding. Modification of the ribosome by the antibiotic resistance enzyme Cfr disrupts stalling due to repositioning of the modified nucleotide. Together, our findings provide molecular understanding for the context-specificity of oxazolidinones.

Synthesis, microbiological evaluation and structure activity relationship analysis of linezolid analogues with different C5-acylamino substituents.

Antimicrobial resistance and lack of new antibiotics to treat multidrug-resistant (MDR) bacteria is a significant public health problem. There is a discovery void and the pipeline of new classes of antibiotics in clinical development is almost empty. Therefore, it is important to understand the structure activity relationships (SAR) of current chemical classes as that can help the drug discovery community in their efforts to develop new antibiotics by modifying existing antibiotic classes. We studied the SAR of the C5-acylaminomethyl moiety of the linezolid, an oxazolidinone antibiotic, by synthesizing 25 compounds containing various aromatic, heteroaromatic and aliphatic substitutions. Our findings suggest that this position is highly important for the function of this antibiotic class, since only smaller non-polar fragments are tolerated at this position while larger and polar ones lead to a decrease in activity compared to linezolid. Our findings have led us to construct a structure activity relationship, around the C5-acylaminomethyl moiety of linezolid, that provides valuable insight into the function of the oxazolidinone class of antibiotics.

Novel Linezolid analogues with antiparasitic activity against Hymenolepis nana.

The stereoselective synthesis and anti- Hymenolepis nana activity of six Linezolid-type compounds, obtained by chemical modification of l-Alanine, are reported in this work. The synthetic strategy was to prepare diasteromeric N,N-dibenzylamino oxazolidinones 1 and 2, and coupling with 4-(4-bromophenyl)morpholine (3) to obtain N,N-dibenzylamino Linezolid analogues 4 and 5. A hydrogenolysis reaction over 4 and 5 resulted in amino-free Linezolid analogues 6 and 7, which were acetylated to reach diasteromeric Linezolid analogues 8 and 9. The six Linezolid analogues 4-9 show in vitro antiparasitic activity against Hymenolepis nana cestode, but not against several bacterial strains. Interestingly, compounds 6, 7 and 9 exhibit high potency, having shorter paralysis and death times after exposure (6-10 and 18-21 min, respectively), shorter than those found with antihelmintic compound Praziquantel (20 and 30 min) at 20 mg/mL. In addition, a cytocompatibility assay of 6-9 with human cells (ARPE-19 cells) demonstrate a non-cytotoxic effect at 0.4 mM. These results show the pharmacological potential of the newly reported Linezolid-type analogues as antiparasitic agents against Hymenolepis nana.

Synergistic Effects of Thiosemicarbazides with Clinical Drugs against S. aureus.

Antimicrobial resistance spurred by the overuse and misuse of antibiotics is a major global health concern, and of the Gram positive bacteria, S. aureus is a leading cause of mortality and morbidity. Alternative strategies to treat S. aureus infections, such as combination therapy, are urgently needed. In this study, a checkerboard method was used to evaluate synergistic interactions between nine thiosemicarbazides (4-benzoyl-1-(2,3-dichloro-benzoyl)thiosemicarbazides 1-5 and 4-aryl-1-(2-fluorobenzoyl)thiosemicarbazides 6-9) and conventional antibiotics against S. aureus ATCC 25923, which were determined as the fractional inhibitory concentration indices (FICIs). For these experiments, amoxicillin, gentamicin, levofloxacin, linezolid, and vancomycin were selected to represent the five antimicrobial classes most commonly used in clinical practice. With one exception of 7-vancomycin combination, none of the forty-five thiosemicarbazide-antibiotic combinations tested had an antagonistic effect, showing promising results with respect to a combination therapy. The synergic effect was observed for the 2-linezolid, 4-levofloxacin, 5-linezolid, 6-gentamicin, 6-linezolid, and 7-levofloxacin combinations. No interactions were seen in combination of the thiosemicarbazide with gentamicin or vancomycin, whereas all combinations with linezolid acted in additive or synergism, except for 6-gentamicin and 7-linezolid. The 4-(4-chlorophenyl)-1-(2-fluorobenzoyl)thiosemicarbazide 6 showed a clear preference for the potency; it affected synergistically in combinations with gentamicin or linezolid and additively in combinations with amoxicillin, levofloxacin, or vancomycin. In further studies, the inhibitory potency of the thiosemicarbazides against S. aureus DNA gyrase and topoisomerase IV was examined to clarify the molecular mechanism involved in their synergistic effect in combination with levofloxacin. The most potent synergist 6 at concentration of 100 µM was able to inhibit ~50% activity of S. aureus DNA gyrase, thereby suggesting that its anti-gyrase activity, although weak, may be a possible factor contributing to its synergism effect in combination with linezolid or gentamycin.

Synergistic Activity of Nitroimidazole-Oxazolidinone Conjugates against Anaerobic Bacteria.

The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen approved recently by the US Food and Drug Administration for the treatment of pulmonary, extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) Mycobacterium tuberculosis (TB). To identify new antimicrobial agents with reduced propensity for the development of resistance, a series of dual-acting nitroimidazole-oxazolidinone conjugates were designed, synthesized and evaluated for their antimicrobial activity. Compounds in this conjugate series have shown synergistic activity against a panel of anaerobic bacteria, including those responsible for serious bacterial infections.

Lipid-polymer hybrid nanoparticles carrying linezolid improve treatment of methicillin-resistant Staphylococcus aureus (MRSA) harbored inside bone cells and biofilms.

Methicillin-resistant Staphylococcus aureus (MRSA) is the most prevalent pathogen causing osteomyelitis. The tendency of MRSA to evade standard antibiotic treatment by hiding inside bone cells and biofilms is a major cause of frequent osteomyelitis recurrence. In this study, we developed a lipid-polymer hybrid nanoparticle loading the antibiotic linezolid (LIN-LPN), and focused on evaluating if this new nanoantibiotic can achieve significant in vitro activities against these intracellular and biofilm-embedded MRSA. The optimal LIN-LPN formulation demonstrated both high linezolid payload (12.0% by weight of nanoparticles) and controlled release characteristics (gradually released the entrapped antibiotic in 120 h). Although it achieved lower activities against bacteria including USA300-0114, CDC-587, RP-62A in planktonic form, it was substantially superior against the intracellular MRSA reservoir inside osteoblast cells. The differences of intracellular activities between LIN-LPN and linezolid were 87.0-fold, 12.3-fold, and 12.6-fold in CFU/ml (p < 0.05 or < 0.01) at 2 µg/ml, 4 µg/ml, and 8 µg/ml linezolid concentrations, respectively. LIN-LPN also suppressed the MRSA biofilm growth to 35-60% of the values achieved with free linezolid (p < 0.05). These enhanced intracellular and anti-biofilm activities of LIN-LPN were likely contributed by the extensive accumulation of LIN-LPN inside the MRSA-infected osteoblasts and biofilms as revealed in the confocal microscope images. The study thus validates the feasibility of exploiting the good nanoparticle-host cell and nanoparticle-biofilm interactions for improving the antibiotic drug activities against the poorly accessible bacteria, and supports LIN-LPN as a new alternative therapy for preventing the recurrence of MRSA-mediated bone infections.

Decision making in the pharmaceutical industry - A tale of three antibiotics.

There is a mounting crisis in treatment of bacterial diseases. The appearance of nosocomial infections produced by multi-drug resistant bacteria is rapidly increasing and at the same time the pharmaceutical industry has been abandoning new antibiotic discovery. To help understand why, we investigated the decision-making processes behind three novel antibiotics that were initially discovered in the late 1980's and early 1990's: daptomycin, linezolid, and lysobactin. Each antibiotic was investigated by two highly qualified scientific organizations that came to opposing opinions regarding the clinical utility and commercial potential of the drug. After reviewing the literature and interviewing key scientific staff members working on each of these molecules, we have identified factors needed to generate positive development decisions. Organizational factors included decision timing, therapeutic area focus, organizational support for risk taking and the presence of a project champion. Technical factors included investment in the optimization of dosing for improved drug exposure, toxicological evaluation of the purified eutomer from a diastereomer and the failure to develop an effective research formulation.

Electrospinning of linezolid loaded PLGA nanofibers: effect of solvents on its spinnability, drug delivery, mechanical properties, and antibacterial activities.

Objective: The choice of a desirable solvent/solvent system is fundamental for optimization of electrospinning by altering the rheological and electrostatic properties of the polymer solutions.Methods: The effects of the solvents and their properties on the viscosity and spinnability of the polymer solutions and the diameter, morphology, in vitro drug release, drug release mechanisms, antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and mechanical properties of electrospun poly-(d,l-lactide-co-glycolide) (PLGA) nanofibers were investigated. Dichloromethane (DCM), dimethylformamide (DMF), various ratios of DCM:DMF, and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) were used as solvents.Results: Although solutions containing DCM/DMF alone were not spinnable, different ratios of DCM:DMF and HFIP were determined as suitable solvents to produce nanofibers because of high enough conductivity, viscosity, and low enough surface tension of the solutions. The DCM:DMF ratio was highly effective on viscosity, nanofiber diameter, morphology, and linezolid release rate. The viscosity of HFIP containing solution was higher and the obtained nanofibers were thicker and smoother with better mechanical properties. The release of nanofibers containing HFIP at a concentration of 10% w/v PLGA was more prolonged than nanofibers containing DCM:DMF mixture. The effect of linezolid content on nanofibers was also investigated. As the amount of linezolid increased, nanofiber diameter and drug release increased and bead formation was observed. While antibacterial activity with nanofibers for which DCM:DMF was used, lasted for 13 days, it was extended to 16 days in nanofibers for which HFIP was used.Conclusions: Type and ratio of the solvent system affected viscosity and spinnability of the solutions, the average nanofiber diameter, morphology, in vitro activity and mechanical properties of the obtained electrospun nanofibers.

Solar-mediated degradation of linezolid and tedizolid under simulated environmental conditions: Kinetics, transformation and toxicity.

Linezolid (LIN) and Tedizolid (TED) are representatives of oxazolidinone antibiotics of last resort with a strong efficacy against gram-positive bacteria. This study focused on their solar-mediated degradation to understand better their fate in aquatic environment, for the realistic concentrations in the range of 1 µg/L. Results showed that both antibiotics (ABs) are degradable by simulated sunlight (1 kW/m2), with half-lives of 32 and 93 h in ultrapure water, for LIN and TED, respectively. LIN showed similar photolytic behaviour in pure solution and in surface water, whereas sunlight enhanced the degradation of LIN in pure solutions, but not in surface water. Structure elucidation by liquid chromatography coupled to high resolution mass spectrometry provided information about seven transformation products for LIN and five for TED. The morpholinyl-ring was identified as the target site for most transformation reactions of LIN. TED was prone to oxidation and cleavage of the oxazolidinone ring. Results of a growth inhibition test on Bacillus subtilis exposed to UV light showed antibacterial efficacy of transformation products of LIN and no significant efficacy of degradation products of TED for the concentration range of 100 µg/L-10 mg/L of parent compounds. Photolytically treated solutions of the ABs maintained their inhibitory effect on the bioluminescence of Aliivibrio fischeri.

A noncanonical binding site of linezolid revealed via molecular dynamics simulations.

Linezolid, an antibiotic of oxazolidinone family, is a translation inhibitor. The mechanism of its action that consists in preventing the binding of aminoacyl-tRNA to the A-site of the large subunit of a ribosome was embraced on the basis of the X-ray structural analysis of the linezolid complexes with vacant bacterial ribosomes. However, the known structures of the linezolid complexes with bacterial ribosomes poorly explain the linezolid selectivity in suppression of protein biosynthesis, depending on the amino acid sequence of the nascent peptide. In the present study the most probable structure of the linezolid complex with a E. coli ribosome in the A,A/P,P-state that is in line with the results of biochemical studies of linezolid action has been obtained by molecular dynamics simulation methods.

Design, synthesis and evaluation of the antibacterial activity of new Linezolid dipeptide-type analogues.

Worldwide studies towards development of new drugs with a lower rate in emergence of bacterial resistance have been conducted. The molecular docking analysis gives a possibility to predict the activity of new compounds before to perform their synthesis. In this work, the molecular docking analysis of 64 Linezolid dipeptide-type analogues was performed to predict their activity. The most negative scores correspond to six Fmoc-protected analogues (9as, 9bs, 9bu, 10as, 10ax and 10ay) where Fmoc group interacts in PTC for Linezolid. Twenty-six different Fmoc-protected Linezolid dipeptide-type analogues 9(as-bz) and 10(as-bz) were synthesized and tested in antimicrobial experiments. Compounds 9as, 9ay, 9ax, 10as, 10ay and 9bu show significant activity against group A Streptococcus clinical isolated. Analogue 10ay also display high activity against ATCC 25923 Staphylococcus aureus strain and MRSA-3, MRSA-4 and MRSA-5 clinical isolates, with MIC values lower than Linezolid. The highest activity against multidrug-resistant clinical isolates of Mycobacterium tuberculosis was exhibited by 9bu. Finally, a cytotoxicity assay with ARPE-19 human cells revealed a non-cytotoxic effect of 9bu and 10ay at 50 and 25 µM, respectively.

Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity.

gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.

Physicochemical Compatibility and Stability of Linezolid with Parenteral Nutrition.

Patients referred to intensive care units (ICU) require special care due to their life-threatening condition, diseases and, frequently, malnutrition. Critically ill patients manifest a range of typical physiological changes caused by predominantly catabolic reactions in the body. It is necessary to provide the patients with proper nutrition, for example by administering total parenteral nutrition (TPN). The addition of linezolid to TPN mixtures for patients treated for linezolid-sensitive infections may reduce the extent of vascular access handling, resulting in a diminished risk of unwanted catheter-related infections. The compatibility and stability studies were conducted of linezolid in parenteral nutrition mixtures of basic, high- and low-electrolytic, high- and low-energetic and immunomodulatory composition. Mixtures containing linezolid were stored at 4⁻6 °C and 25 °C with light protection and at 25 °C without light protection for 168 h. In order to evaluate changes in the concentration of linezolid a previously validated reversed-phase HPLC method with UV detection was used. It was found that linezolid was stable at 4⁻6 °C in the whole course of the study whereas at 25 °C it proved stable over a period of 24 h required for administration of parenteral nutrition mixtures. The TPN mixtures demonstrated compatibility with linezolid and suitable stability, which were not affected by time or storage conditions.

Enantioselective recognition of sutezolid by cyclodextrin modified non-aqueous capillary electrophoresis and explanation of complex formation by means of infrared spectroscopy, NMR and molecular modelling.

A method for the enantioseparation of sutezolid, the next analogue after linezolid and tedizolid, belonging to the truly new class of antibacterial agents, the oxazolidinones, was developed based on non-aqueous capillary electrophoresis (NACE), using a single isomer of cyclodextrins as a chiral pseudophase. During the experiment, the enantioseparation of sutezolid together with its predecessor, linezolid, both weak base antibacterial agents, was evaluated using anionic single-isomers of cyclodextrins from hydrophilic, up to hydrophobic: heptakis-(2,3-dihydroxy-6-sulfo)-ß-cyclodextrin, heptakis-(2,3-diacetyl-6-sulfo)-ß-cyclodextrin (HDAS-ß-CD), as well as heptakis-(2,3-dimethyl-6-sulfo)-ß-cyclodextrin (HDMS-ß-CD), respectively. Based on the observed results, the cyclodextrins, HDAS-ß-CD and HDMS-ß-CD which carry the acetyl and methyl groups at the C2 and C3 positions, respectively, provided the baseline separation of sutezolid enantiomers. However, HDMS-ß-CD led to a reversal of enantiomer migration order (EMO) in comparison to HDAS-ß-CD. Instead, enantiomers of linezolid were separated only by HDMS-ß-CD. During the experiments, different organic solvents and their mixtures in various ratios were tested. The selectivity and separation efficiency were critically affected by the nature of the buffer system, the type of organic solvent, and the concentrations of trifluoroacetic acid (TFA) in the NACE buffer system. Focusing on the desired EMO in which the eutomers (S)-sutezolid and (S)-linezolid migrated last, the highest enantioresolution using the NACE method was achieved at normal polarity mode with 45 mM HDMS-ß-CD dissolved in MeOH/ACN (85:15, v/v) containing 200 mM TFA/20 mM ammonium formate. Moreover, infrared spectroscopy, NMR and molecular modelling were investigated to provide information about complex formation.

Compatibility of linezolid with commercial peritoneal dialysis solutions.

PURPOSE: Results of a compatibility and stability study of linezolid admixed in commercial peritoneal dialysis (PD) solutions stored at various temperatures are reported. METHODS: Test samples were prepared by adding linezolid i.v. injection (2 mg/mL) to infusion bags of 4 PD solutions (Extraneal, Nutrineal, Physioneal 40 Glucose 1.36%, and Physioneal 40 Glucose 2.27%, all from Baxter Healthcare Corporation). Assessments were conducted at various time points during storage of test samples at refrigeration temperature (6 °C) or room temperature (25 °C) for 14 days and at body temperature (37 °C) for 24 hours. Linezolid concentrations over time were determined by high-performance liquid chromatography, physical compatibility was determined by pH measurement and visual inspection, and antimicrobial activity was monitored by a disk diffusion method. The influence of solution warming by heating plate on drug stability was investigated. RESULTS: Linezolid was stable in all tested solutions for 14 days at refrigeration and room temperatures and for 24 hours at body temperature. No linezolid adsorption to container material was detected. There were only minor variations in pH values, and visual inspection revealed no diluent abnormalities. With 1 exception, antimicrobial activity of >90% was retained in all PD solution samples for the duration of the study under all temperature conditions. CONCLUSION: Linezolid injection 2 mg/mL remained stable and was compatible with the PD solutions studied for up to 2 weeks at refrigeration or room temperature and up to 24 hours at body temperature.

Synthesis and antibacterial bioactivities of cationic deacetyl linezolid amphiphiles.

Bacterial infections cause various life-threatening diseases and have become a serious public health problem due to the emergence of drug-resistant strains. Thus, novel antibiotics with excellent antibacterial activity and low cytotoxicity are urgently needed. Here, three series of novel cationic deacetyl linezolid amphiphiles bearing one lipophilic alkyl chain and one non-peptidic amide bond were synthesized and tested for antimicrobial activities. Several compounds showed excellent antibacterial activity toward drug-sensitive bacteria such as gram-negative bacteria Escherichia coli (E. coli), Salmonella enterica (S. enterica) and gram-positive Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis). Moreover, these amphiphilic molecules also exhibited strong activity against drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC (Klebsiella pneumoniae carbapenemase) and NDM-1 (New Delhi metallo-ß-lactamase 1) producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MICs (minimum inhibitory concentrations) of the best compound 6e, ranged from 2 to 16 µg/mL and linezolid ranged from 2 to >64 µg/mL against these strains. Therefore, 6e is a broad-spectrum antimicrobial compound that may be a suitable lead as an antibiotic. The molecule 6e were found to function primarily by permeabilization and depolarization of bacterial membranes. Importantly, bacterial resistance against compound 6e was difficult to induce, and 6e was stable under plasma conditions and showed suitable activity in mammalian plasma. Thus, these compounds can be further developed into a potential new class of broad-spectrum antibiotics.