Search Results (7)

The development of generic ophthalmic drug products with complex formulations is challenging due to the complexity of the ocular system and a lack of sensitive testing to evaluate the interplay of its physiology with ophthalmic drugs. New methods are needed to facilitate the development of ophthalmic generic drug products. Ocular physiologically based pharmacokinetic (O-PBPK) models can provide insight into drug partitioning in eye tissues that are usually not accessible and/or are challenging to sample in humans. This study aims to demonstrate the utility of an ocular PBPK model to predict human exposure following the administration of ophthalmic suspension. Besifloxacin (Bes) suspension is presented as a case study. The O-PBPK model for Bes ophthalmic suspension (Besivance^® 0.6%) accounts for nasolacrimal drainage, suspended particle dissolution in the tears, ocular absorption, and distribution in the rabbit eye. A topical controlled release formulation was used to integrate the effect of Durasite^® on Bes ocular retention. The model was subsequently used to predict Bes exposure after its topical administration in humans. Drug-specific parameters were used as validated for rabbits. The physiological parameters were adjusted to match human ocular physiology. Simulated human ocular pharmacokinetic profiles were compared with the observed ocular tissue concentration data to assess the OCAT models’ ability to predict human ocular exposure. The O-PBPK model simulations adequately described the observed concentrations in the eye tissues following the topical administration of Bes suspension in rabbits. After adjustment of physiological parameters to represent the human eye, the extrapolation of clinical ocular exposure following a single ocular administration of Bes suspension was successful. Full article

The present study applied a nano-synergistic approach to enhance besifloxacin’s potency via nano-formulating besifloxacin on gold nanoparticles (Besi-AuNPs) and adding quercetin as a natural synergistic compound. In fact, a one-pot AuNP synthesis approach was applied for the generation of Besi-AuNPs, where besifloxacin itself acted as a reducing and capping agent. Characterization of Besi-AuNPs was performed by spectrophotometry, DLS, FTIR, and electron microscopy techniques. Moreover, antibacterial assessment of pure besifloxacin, Besi-AuNPs, and their combinations with quercetin were performed on Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. UV-spectra showed a peak of AuNPs at 526 nm, and the electron microscopy-based size was estimated to be 15 ± 3 nm. The effective MIC₅₀ concentrations of besifloxacin after loading on AuNPs were reduced by approximately 50% against the tested bacterial strains. Interestingly, adding quercetin to Besi-AuNPs further enhanced their antibacterial potency, and isobologram analysis showed synergistic potential (combination index below 1) for different quercetin and Besi-AuNP combinations. However, Besi-AuNPs and quercetin combinations were most effective against Gram-positive S. aureus in comparison to Gram-negative P. aeruginosa and E. coli. Their potent activity against S. aureus has its own clinical significance, as it is one the main causative agents of ocular infection, and besifloxacin is primarily used for treating infectious eye diseases. Thus, the outcomes of the present study could be explored further to provide better medication for eye infections caused by resistant pathogens. Full article

Bacterial conjunctivitis significantly impacts public health, including more than one-third of eye diseases reported worldwide. It is an infection caused by various aerobic and anaerobic bacteria and is highly contagious. Therefore, it has a high incidence of bacterial resistance to the antibiotics commonly used for treatment. Among the most recent antibiotics, besifloxacin is a fourth-generation fluoroquinolone antibiotic indicated exclusively for topical ophthalmic use. Due to its importance in treating bacterial conjunctivitis and its low solubility in water, limiting its efficacy, a nanotechnology-based drug delivery preparation was developed to overcome this hurdle. Besifloxacin nanocrystals were prepared by small-scale wet milling and response surface methodology, using Povacoat^® as a stabilizer. The particle’s average hydrodynamic diameter (Z-ave) was approximately 550 nm (17 times smaller than raw material), with a polydispersity index (PdI) of less than 0.2. The saturation solubility increased about two times compared to the raw material, making it possible to increase the dissolution rate of this drug substance, potentially improving its bioavailability and safety. The optimized preparation was stable under an accelerated stability study (90 days). The Z-ave, PZ, PdI, and content did not alter significantly during this period. Furthermore, the 0.6% m/m besifloxacin nanocrystals at the maximum dose and the Povacoat^® stabilizer did not show toxicity in Galleria mellonella larvae. The innovative ophthalmic preparation minimum inhibitory concentration (MIC) was 0.0960 µg/mL and 1.60 µg/mL against Staphylococcus aureus and Pseudomonas aeruginosa, respectively, confirming in vitro efficacy. Therefore, besifloxacin nanocrystals revealed the potential for reduced dosing of the drug substance, with a minor occurrence of adverse effects and greater patient adherence to treatment. Full article

The evolution of the class of antibacterial quinolones includes the introduction in therapy of highly successful compounds. Although many representatives were withdrawn due to severe adverse reactions, a few representatives have proven their therapeutical value over time. The classification of antibacterial quinolones into generations is a valuable tool for physicians, pharmacists, and researchers. In addition, the transition from one generation to another has brought new representatives with improved properties. In the last two decades, several representatives of antibacterial quinolones received approval for therapy. This review sets out to chronologically outline the group of approved antibacterial quinolones since 2000. Special attention is given to eight representatives: besifloxacin, delafoxacin, finafloxacin, lascufloxacin, nadifloxacin and levonadifloxacin, nemonoxacin, and zabofloxacin. These compounds have been characterized regarding physicochemical properties, formulations, antibacterial activity spectrum and advantageous structural characteristics related to antibacterial efficiency. At present these new compounds (with the exception of nadifloxacin) are reported differently, most often in the fourth generation and less frequently in a new generation (the fifth). Although these new compounds’ mechanism does not contain essential new elements, the question of shaping a new generation (the fifth) arises, based on higher potency and broad spectrum of activity, including resistant bacterial strains. The functional groups that ensured the biological activity, good pharmacokinetic properties and a safety profile were highlighted. In addition, these new representatives have a low risk of determining bacterial resistance. Several positive aspects are added to the fourth fluoroquinolones generation, characteristics that can be the basis of the fifth generation. Antibacterial quinolones class continues to acquire new compounds with antibacterial potential, among other effects. Numerous derivatives, hybrids or conjugates are currently in various stages of research. Full article

Background: Besifloxacin ophthalmic suspension 0.6% (w/v%) contains benzalkonium chloride (BAK) as a preservative. We evaluated the in vitro time-kill activity of besifloxacin, alone and in combination with BAK, against common bacteria implicated in ophthalmic infections. Methods: The activity of besifloxacin (100 µg/mL), BAK (10, 15, 20, and 100 µg/mL), and combinations of besifloxacin and BAK were evaluated against isolates of Staphylococcus epidermidis (n = 4), Staphylococcus aureus (n = 3), Haemophilus influenzae (n = 2), and Pseudomonas aeruginosa (n = 2) in time-kill experiments of 180 min duration. With the exception of one S. aureus isolate, all of the staphylococcal isolates were methicillin- and/or ciprofloxacin-resistant; one P. aeruginosa isolate was ciprofloxacin-resistant. The reductions in the viable colony counts (log₁₀ CFU/mL) were plotted against time, and the differences among the time–kill curves were evaluated using an analysis of variance. Areas-under-the-killing-curve (AUKCs) were also computed. Results: Besifloxacin alone demonstrated ≥3-log killing of P. aeruginosa (<5 min) and H. influenzae (<120 min), and approached 3-log kills of S. aureus. BAK alone demonstrated concentration-dependent killing of S. epidermidis, S. aureus and H. influenzae, and at 100 µg/mL produced ≥3-log kills in <5 min against these species. The addition of BAK (10, 15, and 20 µg/mL) to besifloxacin increased the rate of killing compared to besifloxacin alone, with earlier 3-log kills of all species except P. aeruginosa and a variable impact on S. aureus. The greatest reductions in AUKC were observed among H. influenzae (8-fold) and S. epidermidis (≥5-fold). Similar results were found when the isolates were evaluated individually by their resistance phenotype. Conclusions: In addition to confirming the activity of 100 µg/mL BAK as a preservative in the bottle, these data suggest that BAK may help besifloxacin to achieve faster time-kills on-eye in the immediate timeframe post-instillation before extensive dilution against bacterial species implicated in ophthalmic infections, including drug-resistant S. epidermidis. Greater killing activity may help prevent resistance development and/or help treat resistant organisms. Full article

Increasing multidrug-resistance to Gram-positive pathogens, particularly to staphylococci, enterococci and streptococci, is a major problem, resulting in significant morbidity, mortality and healthcare costs. In recent years, only a small number of novel antibiotics effective against Gram-positive bacteria has been approved. This review will discuss the current evidence for novel branded antibiotics that are highly effective in the treatment of multidrug-resistant infections by Gram-positive pathogens, namely ceftobiprole, ceftaroline, telavancin, oritavancin, dalbavancin, tedizolid, besifloxacin, delafloxacin, ozenoxacin, and omadacycline. The mechanism of action, pharmacokinetics, microbiological spectrum, efficacy and safety profile will be concisely presented. As for any emerging antibiotic agent, resistance is likely to develop against these highly effective antibiotics. Only through appropriate dosing, utilization and careful resistance development monitoring will these novel antibiotics continue to treat Gram-positive pathogens in the future. Full article

In this paper (R)-7-(azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1 was isolated and identified as the N-substituted regioisomer of besifloxacin, which has been synthesized from the reaction of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3 with (R)-tert-butyl 3-aminoazepane-1-carboxylate 2 in acetonitrile as solvent in 37% yield. The chemical structure of compound 1 was established on the basis of ¹H-NMR, ¹³C-NMR, mass spectrometry data and elemental analysis. Full article